Inhibitors of semicarbazide-sensitive amine oxidase (SSAO) and VAP-1 mediated adhesion useful for treatment and prevention of diseases

ABSTRACT

Compositions and methods of using compositions for treatment of inflammatory diseases and immune disorders are provided. Allylamino compounds are disclosed which are inhibitors of semicarbazide-sensitive amine oxidase (SSAO) and/or vascular adhesion protein 1 (VAP-1). The compounds have therapeutic utility in suppressing inflammation and inflammatory responses, and in treatment of several disorders, including multiple sclerosis and stroke.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the priority benefit of U.S. Provisional PatentApplication No. 60/787,751 filed Mar. 31, 2006, U.S. Provisional PatentApplication No. 60/834,016 filed Jul. 28, 2006, and U.S. ProvisionalPatent Application No. 60/855,481 filed Oct. 30, 2006. The contents ofthose applications are hereby incorporated herein by reference in theirentirety.

TECHNICAL FIELD

This application relates to compositions and methods for inhibitingsemicarbazide-sensitive amine oxidase (SSAO), also known as vascularadhesion protein-1 (VAP-1), for treatment and prevention ofinflammation, inflammatory diseases and autoimmune disorders.

BACKGROUND

Human vascular adhesion protein-1 (VAP-1) is a type 2, 180 kDhomodimeric endothelial cell adhesion molecule. Cloning and sequencingof VAP-1 revealed that the VAP-1 cDNA sequence is identical to that ofthe previously known protein semicarbazide-sensitive amine oxidase(SSAO), a copper-containing amine oxidase. The precise difference (ifany) between the membrane-bound VAP-1 adhesion protein and the solubleSSAO enzyme has not yet been determined; one hypothesis indicates thatproteolytic cleavage of the membrane-bound VAP-1 molecule results in thesoluble SSAO enzyme. Both the membrane-bound VAP-1 protein and thesoluble SSAO enzyme have amine oxidase enzymatic activity. Thusmembrane-bound VAP-1 can function both as an amine oxidase and a celladhesion molecule.

Semicarbazide-sensitive amine oxidase is a member of a group of enzymes;that group is referred to generically as semicarbazide-sensitive amineoxidases (SSAOs). SSAOs are mostly soluble enzymes that catalyzeoxidative deamination of primary amines. The reaction results in theformation of the corresponding aldehyde and release of H₂O₂ andammonium. These enzymes are different from monoamine oxidases A and B(MAO-A and MAO-B, respectively), in terms of their substrates,inhibitors, cofactors, subcellular localization and function. To date,no physiological function has been definitively associated with SSAOs,and even the nature of the physiological substrates is not firmlyestablished (reviewed in Buffoni F. and Ignesti G. (2000) Mol. GeneticsMetabl. 71:559-564). However, they have been implicated in themetabolism of exogenous and endogenous amines and in the regulation ofglucose transport.

SSAO molecules are highly conserved across species; the closesthomologue to the human protein is the bovine serum amine oxidase (about85% identity). Substrate specificity and tissue distribution varyconsiderably among different species. In humans, SSAO specific activityhas been detected in most tissues but with marked differences (highestin aorta and lung). Human and rodent plasma have very low SSAO activitycompared with ruminants. Depletion studies suggest that SSAO/VAP-1accounts for ˜90% of cell and serum SSAO activity (Jaakkola K. et al.(1999) Am. J. Pathol. 155:1953).

Membrane-bound VAP-1 is primarily expressed in high endothelial cells(ECs) of lymphatic organs, sinusoidal ECs of the liver and small calibervenules of many other tissues. Moreover, SSAO/VAP-1 is also found indendritic cells of germinal centers and is abundantly present inadipocytes, pericytes and smooth muscle cells. However, it is absentfrom capillaries, ECs of large blood vessels, epithelial cells,fibroblasts and leukocytes other than dendritic cells (Salmi M. et al.(2001) Trends Immunol. 22:211). Studies in clinical samples revealedthat SSAO/VAP-1 is upregulated on vasculature at many sites ofinflammation, such as synovitis, allergic and other skin inflammations,and inflammatory bowel disease (IBD). However, expression appears to becontrolled by additional mechanisms. Animal studies indicate that theluminal SSAO/VAP-1 is induced only upon elicitation of inflammation.Thus, in ECs, SSAO/VAP-1 is stored in intracellular granules and istranslocated onto the luminal surface only at sites of inflammation.

In the serum of healthy adults a soluble form of SSAO/VAP-1 is found ata concentration of 80 ng/ml. Soluble SSAO/VAP-1 levels increase incertain liver diseases and in diabetes, but remain normal in many otherinflammatory conditions. Soluble SSAO/VAP-1 has an N-terminal amino acidsequence identical to the proximal extracellular sequence of themembrane bound form of SSAO/VAP-1. In addition, there is good evidencethat at least a significant portion of the soluble molecule is producedin the liver by proteolytic cleavage of sinusoidal VAP-1 (Kurkijarvi R.et al. (2000) Gastroenterology 119:1096).

SSAO/VAP-1 regulates leukocyte adhesion to ECs. Studies show thatSSAO/VAP-1 is involved in the adhesion cascade at sites whereinduction/activation of selectins, chemokines, immunoglobulinsuperfamily molecules, and integrins takes place. In the appropriatecontext, nevertheless, inactivation of SSAO/VAP-1 function has anindependent and significant effect on the overall extravasion process. Arecent study shows that both the direct adhesive and enzymatic functionsof SSAO/VAP-1 are involved in the adhesion cascade (Salmi M. et al.(2001) Immunity 14:265). In this study, it was proposed that the SSAOactivity of VAP-1 is directly involved in the pathway of leukocyteadhesion to endothelial cells by a novel mechanism involving directinteraction with an amine substrate presented on a VAP-1 ligandexpressed on the surface of a leukocyte. Under physiological laminarshear, it seems that SSAO/VAP-1 first comes into play after tethering(which takes place via binding of selectins to their ligands) whenlymphocytes start to roll on ECs. Accordingly, anti-VAP-1 monoclonalantibodies inhibit ˜50% of lymphocyte rolling and significantly reducethe number of firmly bound cells. In addition, inhibition of VAP-1enzymatic activity by SSAO inhibitors, also results in a >40% reductionin the number of rolling and firmly bound lymphocytes. Thus, inhibitorsof SSAO/VAP-1 enzymatic activity could reduce leukocyte adhesion inareas of inflammation and thereby reduce leukocyte trafficking into theinflamed region and, consequently, reduce the inflammatory processitself.

Increased SSAO activity has been found in the plasma and islets of TypeI and Type II diabetes patients and animal models, as well as aftercongestive heart failure, and in an atherosclerosis mouse model (SalmiM,. et al. (2002) Am. J. Pathol. 161:2255; Bono P. et al (1999) Am. J.Pathol. 155:1613; Boomsma F. et al (1999) Diabetologia 42:233;Gronvall-Nordquist J. et al (2001) J. Diabetes Complications 15:250;Ferre I. et al. (2002) Neurosci. Lett. 15; 321: 21; Conklin D. J. et al.(1998) Toxicological Sciences 46: 386; Yu P. H. and Deng Y. L. (1998)Atherosclerosis 140:357; Vidrio H. et al. (2002) General Pharmacology35:195; Conklin D. J. (1999) Toxicology 138: 137). In addition toupregulation of expression of VAP-1 in the inflamed joints of rheumatoidarthritis (RA) patients and in the venules from lamina propria andPeyer's patches of IBD patients, increased synthesis of VAP-1 was alsofound in chronic skin inflammation and liver disease (Lalor P. F. et al.(2002) J. Immunol. 169:983; Jaakkola K. et al. (2000) Am. J. Pathol.157:463; Salmi M. and Jalkanen S. (2001) J. Immunol. 166:4650; Lalr P.F. et al. (2002) Immunol Cell Biol 80:52; Salmi M et al. (1997) J. Clin.Invest. 99:2165; Kurkijarvi R. et al. (1998) J. Immunol. 161:1549).

In summary, SSAO/VAP-1 is an inducible endothelial enzyme that mediatesthe interaction between leukocytes and inflamed vessels. The fact thatSSAO/VAP-1 has both enzymatic and adhesion activities together with thestrong correlation between its upregulation in many inflammatoryconditions, makes it a potential therapeutic target for all theabove-mentioned disease conditions.

DISCLOSURE OF THE INVENTION

SSAO inhibitors can block inflammation and autoimmune processes, as wellas other pathological conditions associated with an increased level ofthe circulating amine substrates and/or products of SSAO. In oneembodiment, the invention relates to a method of inhibiting aninflammatory response by administration of compounds to inhibit SSAOenzyme activity (where the enzyme activity is due either to soluble SSAOenzyme or membrane-bound VAP-1 protein, or due to both) and/or inhibitbinding to VAP-1 protein. In another embodiment, the inflammatoryresponse is an acute inflammatory response. In another embodiment, theinvention relates to treating or preventing diseases mediated at leastin part by SSAO or VAP-1, as generally indicated by one or more ofabnormal levels of SSAO and/or VAP-1 or abnormal activity of SSAO and/orVAP-1 (where the abnormal activity of VAP-1 may affect its bindingfunction, its amine oxidase function, or both), by administering atherapeutically effective amount of an SSAO inhibitor, or administeringa therapeutically effective combination of SSAO inhibitors. In anotherembodiment, the invention relates to a method of treating or preventingimmune disorders, by administering a therapeutically effective amount ofan SSAO inhibitor, or administering a therapeutically effectivecombination of SSAO inhibitors. In another embodiment, the inventionrelates to a method of treating or preventing multiple sclerosis(including chronic multiple sclerosis), by administering atherapeutically effective amount of an SSAO inhibitor, or administeringa therapeutically effective combination of SSAO inhibitors. In anotherembodiment, the invention relates to a method of treating or preventingischemic diseases (for example, stroke) and/or the sequelae thereof (forexample, an inflammatory response), by administering a therapeuticallyeffective amount of an SSAO inhibitor, or administering atherapeutically effective combination of SSAO inhibitors. The SSAOinhibitors administered can inhibit the SSAO activity of soluble SSAO,the SSAO activity of membrane-bound VAP-1, binding to membrane-boundVAP-1, or any two of those activities, or all three of those activities.In another embodiment, the invention relates to a method of inhibitingSSAO activity or inhibiting binding to VAP-1 in vitro using thecompounds provided herein. In another embodiment, the invention relatesto a method of inhibiting SSAO activity or inhibiting binding to VAP-1in vivo, that is, in a living organism, such as a vertebrate, mammal, orhuman, using the compounds provided herein.

In another embodiment, the present invention relates to variouscompounds which are useful for inhibiting SSAO enzyme activity (wherethe enzyme activity is due either to soluble SSAO enzyme ormembrane-bound VAP-1 protein, or due to both) and/or inhibition ofbinding to membrane-bound VAP-1 protein. In another embodiment, thepresent invention relates to methods of using various compounds toinhibit SSAO enzyme activity (where the enzyme activity is due either tosoluble SSAO enzyme or membrane-bound VAP-1 protein, or due to both). Inanother embodiment, the present invention relates to methods ofinhibiting binding to VAP-1 protein.

In another embodiment, the present invention relates to methods oftreating or preventing inflammation, by administering an SSAO inhibitorwhich has a specificity for inhibition of SSAO as compared to MAO-Aand/or MAO-B, of about 10-fold, greater than about 10-fold, about100-fold, greater than about 100-fold, about 500-fold, greater thanabout 500-fold, about 1,000-fold, greater than about 1000-fold, about5,000-fold, or greater than about 5000-fold.

In another embodiment, the present invention relates to methods oftreating or preventing an immune or autoimmune disorder, byadministering an SSAO inhibitor which has a specificity for inhibitionof SSAO as compared to MAO-A and/or MAO-B of about 10-fold, greater thanabout 10-fold, about 100-fold, greater than about 100-fold, about500-fold, greater than about 500-fold, about 1,000-fold, greater thanabout 1000-fold, about 5,000-fold, or greater than about 5000-fold.

In another embodiment, the present invention relates to methods oftreating or preventing inflammation, by administering an SSAO inhibitorwhich has a specificity for inhibition of SSAO as compared to diamineoxidase of about 10-fold, greater than about 10-fold, about 100-fold,greater than about 100-fold, about 500-fold, greater than about500-fold, about 1,000-fold, greater than about 1000-fold, about5,000-fold, or greater than about 5000-fold.

In another embodiment, the present invention relates to methods oftreating or preventing an immune or autoimmune disorder, byadministering an SSAO inhibitor which has a specificity for inhibitionof SSAO as compared to diamine oxidase of about 10-fold, greater thanabout 10-fold, about 100-fold, greater than about 100-fold, about500-fold, greater than about 500-fold, about 1,000-fold, greater thanabout 1000-fold, about 5,000-fold, or greater than about 5000-fold.

The inflammation or inflammatory disease or immune or autoimmunedisorder to be treated by the SSAO inhibitors of the specificityindicated may be, or may be caused by, multiple sclerosis (includingchronic multiple sclerosis); synovitis; systemic inflammatory sepsis;inflammatory bowel diseases; Crohn's disease; ulcerative colitis;Alzheimer's disease; vascular dementia; atherosclerosis; rheumatoidarthritis; juvenile rheumatoid arthritis; pulmonary inflammatoryconditions; asthma; skin inflammatory conditions and diseases; contactdermatitis; liver inflammatory and autoimmune conditions; autoimmunehepatitis; primary biliary cirrhosis; sclerosing cholangitis; autoimmunecholangitis; alcoholic liver disease; Type I diabetes and/orcomplications thereof; Type II diabetes and/or complications thereof;atherosclerosis; chronic heart failure; congestive heart failure;ischemic diseases such as stroke and/or complications thereof, andmyocardial infarction and/or complications thereof. In anotherembodiment, the inflammatory disease or immune disorder to be treated orprevented by the present invention is multiple sclerosis (includingchronic multiple sclerosis). In another embodiment, the inflammatorydisease or immune disorder to be treated or prevented by the presentinvention is stroke or the inflammatory complications resulting fromstroke.

In another embodiment, the present invention relates to methods oftreating or preventing inflammation, by administering one or morecompounds of formula I, I-P, I-E, I-P-E, I-P-Z, I-A, I-AP, I-A-E,I-AP-E, I-A-Z, I-AP-Z, I-B, I-BP, I-B-E, I-BP-E, I-B-Z, I-BP-Z, any oneof I-1 through I-109, II, II-E, II-Z, II-A, II-A-E, II-A-Z, II-B,II-B-E, II-B-Z, any one of II-1 through II-23, IV, and any one of IV-1through IV-10 as described herein in a therapeutically effective amount,or in an amount sufficient to treat or prevent inflammation. In anotherembodiment, the present invention relates to methods of treating orpreventing immune or autoimmune disorders, by administering one or morecompounds of formula I, I-P, I-E, I-P-E, I-P-Z, I-A, I-AP, I-A-E,I-AP-E, I-A-Z, I-AP-Z, I-B, I-BP, I-B-E, I-BP-E, I-B-Z, I-BP-Z, any oneof I-1 through I-109, II, II-E, II-Z, II-A, II-A-E, II-A-Z, II-B,II-B-E, II-B-Z, any one of II-1 through II-23, IV, and any one of IV-1through IV-10 described herein in a therapeutically effective amount, orin an amount sufficient to treat or prevent an immune or autoimmunedisorder.

In another embodiment, the present invention relates to methods oftreating or preventing inflammation, by administering one or more of thecompounds I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12,I-13, I-14, I-15, I-16, I-17, I-18, I-19, I-20, I-21, I-22, I-23, I-24,I-25, I-26, I-27, I-28, I-29, I-30, I-31, I-32, I-33, I-34, I-35, I-36,I-37, I-38, I-39, I-40, I-41, I-42, I-43, I-44, I-45, I-46, I-47, I-48,I-49, I-50, I-51, I-52, I-53, I-54, I-55, I-56, I-57, I-58, I-59, I-60,I-61, I-62, I-63, I-64, I-65, I-66, I-67, I-68, I-69, I-70, I-71, I-72,I-73, I-74, I-75, I-76, I-77, I-78, I-79, I-80, I-81, I-82, I-83, I-84,I-85, I-86, I-87, I-88, I-89, I-90, I-91, I-92, I-93, I-94, I-95, I-96,I-97, I-98, I-99, I-100, I-101, I-102, I-103, I-104, I-105, I-106,I-107, I-108, I-109, II-1, II-2, II-3, II-4, II-5, II-6, II-7, II-8,II-9, II-10, II-11, II-12, II-13, II-14, II-15, II-16, II-17, II-18,II-19, II-20, II-21, II-22, II-23, IV-1, IV-2, IV-3, IV-4, IV-5, IV-6,IV-7, IV-8, IV-9, or IV-10 described herein in a therapeuticallyeffective amount, or in an amount sufficient to treat or preventinflammation. In another embodiment, the present invention relates tomethods of treating or preventing immune or autoimmune disorders, byadministering one or more of the compounds I-1, I-2, I-3, I-4, I-5, I-6,I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-15, I-16, I-17, I-18,I-19, I-20, I-21, I-22, I-23, I-24, I-25, I-26, I-27, I-28, I-29, I-30,I-31, I-32, I-33, I-34, I-35, I-36, I-37, I-38, I-39, I-40, I-41, I-42,I-43, I-44, I-45, I-46, I-47, I-48, I-49, I-50, I-51, I-52, I-53, I-54,I-55, I-56, I-57, I-58, I-59, I-60, I-61, I-62, I-63, I-64, I-65, I-66,I-67, I-68, I-69, I-70, I-71, I-72, I-73, I-74, I-75, I-76, I-77, I-78,I-79, I-80, I-81, I-82, I-83, I-84, I-85, I-86, I-87, I-88, I-89, I-90,I-91, I-92, I-93, I-94, I-95, I-96, I-97, I-98, I-99, I-100, I-101,I-102, I-103, I-104, I-105, I-106, I-107, I-108, I-109, II-1, II-2,II-3, II-4, II-5, II-6, II-7, II-8, II-9, II-10, II-11, II-12, II-13,II-14, II-15, II-16, II-17, II-18, II-19, II-20, II-21, II-22, II-23,IV-1, IV-2, IV-3, IV-4, IV-5, IV-6, IV-7, IV-8, IV-9, or IV-10 describedherein in a therapeutically effective amount, or in an amount sufficientto treat or prevent an immune or autoimmune disorder.

In another embodiment, the invention relates to compounds of formula I:

wherein Y is aryl or heteroaryl optionally substituted with one or moregroups of the form R₁, wherein each R₁ is independently selected fromC₁-C₈ alkyl, C₃-C₈ cycloalkyl, —O—C₁-C₈ alkyl, —O—C₃-C₈ cycloalkyl,—C₆-C₁₀ aryl, —O—C₁-C₄ alkyl-C₆-C₁₀ aryl, —S—C₁-C₈ alkyl, —CF₃, —S—CF₃,—OCF₃, —OCH₂CF₃, F, Cl, Br, I, —NO₂, —OH, —CN, —NR₅R₆, —NHR₇, and—S(O₂)—(C₁-C₈ alkyl); R₂ is selected from H, F, Cl, C₁-C₄ alkyl, and—CF₃; R₃ and R₄ are independently selected from H, —C₁-C₈ alkyl, —C₁-C₄alkyl-C₆-C₁₀ aryl, or R₃ and R₄ together with the nitrogen to which theyare attached form a nitrogen-containing ring (including, but not limitedto, morpholino, piperidino, and piperazino); R₅ and R₆ are independentlyselected from H, —C₁-C₈ alkyl, —C₁-C₄ alkyl-C₆-C₁₀ aryl, or R₅ and R₆together with the nitrogen to which they are attached form anitrogen-containing ring (including, but not limited to, morpholino,piperidino, and piperazino); R₇ is selected from —C(═O)—(C₁-C₈ alkyl)and —C(═O)—(C₆-C₁₀ aryl); X is —CH₂—, —O—, or —S—; n is 0, 1, 2, or 3.In another embodiment, R₁ is selected from C₁-C₄ alkyl, —O—C₁-C₄ alkylor —S—C₁-C₈ alkyl; and any stereoisomer, mixture of stereoisomers,prodrug, metabolite, crystalline form, non-crystalline form, hydrate,solvate, or salt thereof.

In another embodiment, formula I is subject to the proviso that when Yis phenyl, R₃ and R₄ are both H, X is CH₂, and n is 0, then there is atleast one R₁ substituent. In another embodiment, formula I is subject tothe proviso that when Y is phenyl, R₃ and R₄ are both H, X is CH₂, and nis 0, then if at least one R₁ substituent is —OCH₃, then there is atleast one additional R₁ substituent which is not —OCH₃. In anotherembodiment, formula I is subject to the proviso that when Y is phenyl,R₃ and R₄ are both H, X is CH₂, and n is 0, then if at least one R₁substituent is —OH, then there is at least one additional R₁ substituentwhich is not —OH.

In another embodiment, formula I is subject to the proviso that when Yis phenyl, R₃ and R₄ are both H, X is O or S, and n is 1, then there isat least one R₁ substituent. In another embodiment, formula I is subjectto the proviso that when Y is phenyl, R₃ and R₄ are both H, X is O or S,and n is 1, then the phenyl substituents are not Cl, —CF₃, or F in theortho or para position. In another embodiment, formula I is subject tothe proviso that when Y is phenyl, R₃ and R₄ are both H, X is O or S,and n is 1, then the phenyl substituents are not 3-chloro-5-fluoro. Inanother embodiment, formula I is subject to the proviso that when Y isphenyl, R₃ and R₄ are both H, X is O or S, and n is 1, then if at leastone R₁ substituent is —OCH₃, then there is at least one additional R₁substituent is not —OCH₃. In another embodiment, formula I is subject tothe proviso that when Y is phenyl, R₃ and R₄ are both H, X is O or S,and n is 1, if at least one R₁ substituent is —OH, then there is atleast one additional R₁ substituent which is not —OH.

In another embodiment, formula I is subject to the proviso that when Yis phenyl, R₃ and R₄ are both H, X is CH₃, and n is 1, then there is atleast one R₁ substituent. In another embodiment, formula I is subject tothe proviso that when Y is phenyl, R₃ and R₄ are both H, X is CH₃, and nis 1, then the phenyl substituent is not F in the para position.

In another embodiment, formula I is subject to the proviso that when Yis phenyl, R₃ and R₄ are both H, X is CH₃, and n is 2, then the phenylsubstituents are not 3,4-dimethoxy.

The compounds of formula I with provisos are designated as compounds offormula I-P.

In another embodiment, X is CH₂ and n is 0 or 1. In another embodiment,X is CH₂ and n is 0. In another embodiment, X is CH₂ and n is 1. Inanother embodiment of the compounds of formula I, Y is phenyl,optionally substituted with one or more R₁ substituents. In anotherembodiment R₃ and R₄ are both H. In another embodiment, R₂ is F. Inanother embodiment, R₂ is Cl. In another embodiment, X is O and n is 0.

In another embodiment, the compounds of formula I or I-P are in the Econfiguration of the double bond; those compounds are designated ascompounds of formula I-E or I-P-E, respectively. In another embodiment,the compounds of formula I or I-P are in the Z configuration of thedouble bond; those compounds are designated as compounds of formula I-Zor I-P-Z, respectively.

In another embodiment, the invention relates to compounds of formulaI-A:

wherein each R₁ is independently selected from H, C₁-C₈ alkyl, C₃-C₈cycloalkyl, —O—C₁-C₈ alkyl, —O—C₃-C₈ cycloalkyl, —C₆-C₁₀ aryl, —O—C₁-C₄alkyl-C₆-C₁₀ aryl, —S—C₁-C₈ alkyl, —CF₃, —OCF₃, —S—CF₃, —OCH₂CF₃, F, Cl,Br, I, —NO₂, —OH, —CN, —NR₅R₆, —NHR₇, and —S(O₂)—(C₁-C₈ alkyl); R₂ isselected from H, F, Cl, C₁-C₄ alkyl, and —CF₃; R₃ and R₄ areindependently selected from H, —C₁-C₈ alkyl, —C₁-C₄ alkyl-C₆-C₁₀ aryl,or R₃ and R₄ together with the nitrogen to which they are attached forma nitrogen-containing ring (including, but not limited to, morpholino,piperidino, and piperazino); R₅ and R₆ are independently selected fromH, —C₁-C₈ alkyl, —C₁-C₄ alkyl-C₆-C₁₀ aryl, or R₅ and R₆ together withthe nitrogen to which they are attached form a nitrogen-containing ring(including, but not limited to, morpholino, piperidino, and piperazino);R₇ is selected from —C(═O)—(C₁-C₈ alkyl) and —C(═O)—(C₆-C₁₀ aryl); X is—CH₂—, —O—, or —S—; n is 0, 1, 2, or 3; and p is 0, 1, 2, or 3; and anystereoisomer, mixture of stereoisomers, prodrug, metabolite, crystallineform, non-crystalline form, hydrate, solvate, or salt thereof.

In another embodiment, formula I-A is subject to the proviso that whenR₃ and R₄ are both H, X is CH₂, and n is 0, then there is at least oneR₁ substituent. In another embodiment, formula I-A is subject to theproviso that when R₃ and R₄ are both H, X is CH₂, and n is 0, then if atleast one R₁ substituent is —OCH₃, then there is at least one additionalR₁ substituent which is not —OCH₃. In another embodiment, formula I-A issubject to the proviso that when R₃ and R₄ are both H, X is CH₂, and nis 0, then if at least one R₁ substituent is —OH, then there is at leastone additional R₁ substituent which is not —OH.

In another embodiment, formula I-A is subject to the proviso that whenR₃ and R₄ are both H, X is O or S, and n is 1, then there is at leastone R₁ substituent. In another embodiment, formula I-A is subject to theproviso that when R₃ and R₄ are both H, X is O or S, and n is 1, thenthe phenyl substituents are not Cl, —CF₃, or F in the ortho or paraposition. In another embodiment, formula I-A is subject to the provisothat when R₃ and R₄ are both H, X is O or S, and n is 1, then the phenylsubstituents are not 3-chloro-5-fluoro. In another embodiment, formulaI-A is subject to the proviso that when R₃ and R₄ are both H, X is O orS, and n is 1, then if at least one R₁ substituent is —OCH₃, then thereis at least one additional R₁ substituent is not —OCH₃. In anotherembodiment, formula I-A is subject to the proviso that when R₃ and R₄are both H, X is O or S, and n is 1, then if at least one R₁ substituentis —OH, then there is at least one additional R₁ substituent which isnot —OH.

In another embodiment, formula I-A is subject to the proviso that whenR₃ and R₄ are both H, X is CH₃, and n is 1, then there is at least oneR₁ substituent. In another embodiment, formula I-A is subject to theproviso that when R₃ and R₄ are both H, X is CH₃, and n is 1, then thephenyl substituent is not F in the para position.

The compounds of formula I-A with provisos are designated as compoundsof formula I-AP.

In another embodiment, the compounds of formula I-A or I-AP are in the Econfiguration of the double bond; those compounds are designated ascompounds of formula I-A-E or I-AP-E, respectively. In anotherembodiment, the compounds of formula I-A or I-AP are in the Zconfiguration of the double bond; those compounds are designated ascompounds of formula I-AZ or I-AP-Z, respectively.

In one embodiment of the compounds of formula I-A, X is CH₂ and n is 0or 1. In another embodiment, X is CH₂ and n is 0. In another embodiment,X is CH₂ and n is 1. In another embodiment, R₃ and R₄ are both H. Inanother embodiment, R₂ is F. In another embodiment, R₂ is Cl. In anotherembodiment, X is O and n is 0.

In another embodiment, the invention relates to compounds of formulaI-B:

wherein each R₁ is independently selected from H, C₁-C₈ alkyl, C₃-C₈cycloalkyl, —O—C₁-C₈ alkyl, —O—C₃-C₈ cycloalkyl, —C₆-C₁₀ aryl, —O—C₁-C₄alkyl-C₆-C₁₀ aryl, —S—C₁-C₈ alkyl, —CF₃, —OCF₃, —S—CF₃, —OCH₂CF₃, F, Cl,Br, I, —NO₂, —OH, —CN, —NR₅R₆, —NHR₇, and —S(O₂)—(C₁-C₈ alkyl); R₂ isselected from H, F, Cl, C₁-C₄ alkyl, and —CF₃; R₅ and R₆ areindependently selected from H, —C₁-C₈ alkyl, —C₁-C₄ alkyl-C₆-C₁₀ aryl,or R₅ and R₆ together with the nitrogen to which they are attached forma nitrogen-containing ring (including, but not limited to, morpholino,piperidino, and piperazino); R₇ is selected from —C(═O)—(C₁-C₈ alkyl)and —C(═O)—(C₆-C₁₀ aryl); X is —CH₂— or —O—; n is 0, 1, 2, or 3; and pis 0, 1, 2, or 3; and any stereoisomer, mixture of stereoisomers,prodrug, metabolite, crystalline form, non-crystalline form, hydrate,solvate, or salt thereof.

In another embodiment, formula I-B is subject to the proviso that when Xis CH₂, and n is 0, then there is at least one R₁ substituent. Inanother embodiment, formula I-B is subject to the proviso that when X isCH₂, and n is 0, then if at least one R₁ substituent is —OCH₃, thenthere is at least one additional R₁ substituent which is not —OCH₃. Inanother embodiment, formula I-B is subject to the proviso that when X isCH₂, and n is 0, then if at least one R₁ substituent is —OH, then thereis at least one additional R₁ substituent which is not —OH.

In another embodiment, formula I-B is subject to the proviso that when Xis O or S, and n is 1, then there is at least one R₁ substituent. Inanother embodiment, formula I-B is subject to the proviso that when X isO or S, and n is 1, then the phenyl substituents are not Cl, —CF₃, or Fin the ortho or para position. In another embodiment, formula I-B issubject to the proviso that when X is O or S, and n is 1, then phenylsubstituents are not 3-chloro-5-fluoro. In another embodiment, formulaI-B is subject to the proviso that when X is O or S, and n is 1, then ifat least one R₁ substituent is —OCH₃, then there is at least oneadditional R₁ substituent which is not —OCH₃. In another embodiment,formula I-B is subject to the proviso that when X is O or S, and n is 1,then if at least one R₁ substituent is —OH, then there is at least oneadditional R₁ substituent which is not —OH.

In another embodiment, formula I-B is subject to the proviso that when Xis CH₃, and n is 1, then there is at least one R₁ substituent. Inanother embodiment, formula I-B is subject to the proviso that when X isCH₃, and n is 1, then the phenyl substituent is not F in the paraposition.

The compounds of formula I-B with provisos are designated as compoundsof formula I-BP.

In another embodiment, the compounds of formula I-B or I-BP are in the Econfiguration of the double bond; those compounds are designated ascompounds of formula I-B-E or I-BP-E, respectively. In anotherembodiment, the compounds of formula I-B or I-BP are in the Zconfiguration of the double bond; those compounds are designated ascompounds of formula I-BZ or I-BP-Z, respectively.

In another embodiment of the compounds of formula I-B, X is CH₂ and n is0 or 1. In another embodiment, X is CH₂ and n is 0. In anotherembodiment, X is CH₂ and n is 1. In another embodiment, R₂ is F. Inanother embodiment, R₂ is Cl. In another embodiment, X is 0 and n is 0.

In one embodiment of the compounds of formula I, I-P, I-E, I-P-E, I-Z,I-P-Z, I-A, I-AP, I-A-E, I-AP-E, I-A-Z, I-AP-Z, I-B, I-BP, I-B-E,I-BP-E, I-B-Z, or I-BP-Z, n is 0. In another embodiment, R₁ is selectedfrom C₁-C₄ alkyl or —O—C₁-C₄ alkyl. In another embodiment, n is 0 and Xis —CH₂—. In another embodiment, n is 0, X is —CH₂—, and R₅ and R₆ are Hor —C₁-C₈ alkyl. In another embodiment, n is 0, X is —CH₂—, R₅ and R₆are H or —C₁-C₈ alkyl, and each R₁ is independently selected from H,C₁-C₄ alkyl, C₃-C₈ cycloalkyl, —O—C₁-C₄ alkyl, —S—C₁-C₄ alkyl, CF₃,—OCF₃, F, and Cl. In another embodiment, n is 0, X is —CH₂—, R₅ and R₆are H or —C₁-C₈ alkyl, each R₁ is independently selected from H, C₁-C₄alkyl, C₃-C₈ cycloalkyl, —O—C₁-C₄ alkyl, —S—C₁-C₈ alkyl, CF₃, —OCF₃, F,and Cl, and p is 1 or 2. In another embodiment, n is 0, X is —CH₂—, R₅and R₆ are H or —C₁-C₈ alkyl, and each R₁ is independently selected fromH, C₁-C₄ alkyl, —S—C₁-C₄ alkyl, and —O—C₁-C₄ alkyl. In anotherembodiment, n is 0, X is —CH₂—, R₅ and R₆ are H or —C₁-C₈ alkyl, each R₁is independently selected from H, C₁-C₄ alkyl, —S—C₁-C₄ alkyl, and—O—C₁-C₄ alkyl, and p is 1 or 2. In another embodiment, n is 0, X is—CH₂—, R₅ and R₆ are H or —C₁-C₈ alkyl, each R₁ is independentlyselected from H, C₁-C₄ alkyl, —S—C₁-C₄ alkyl, and —O—C₁-C₄ alkyl, and pis 1.

In another embodiment, the present invention relates to any one of thecompounds of general formula I of the formula:

or any stereoisomer, mixture of stereoisomers, prodrug, metabolite,crystalline form, non-crystalline form, hydrate, solvate, or saltthereof.

In another embodiment, the present invention relates to any one of thecompounds of general formula I:

-   I-1-Z: (Z)-3 -fluoro-2-(4-methoxybenzyl)prop-2-en-1-amine,-   I-2-Z: (Z)-2-(4-ethoxybenzyl)-3-fluoroprop-2-en-1-amine,-   I-3-Z: (Z)-2-(4-chlorobenzyl)-3-fluoroprop-2-en-1-amine,-   I-4-Z: (Z)-2-(3-chlorobenzyl)-3-fluoroprop-2-en-1-amine,-   I-5-Z: (Z)-3-fluoro-2-(3-methoxybenzyl)prop-2-en-1-amine,-   I-6-Z: (Z)-2-(3,4-dimethoxybenzyl)-3-fluoroprop-2-en-1-amine,-   I-7-Z: (Z)-2-(3,5-dimethoxybenzyl)-3-fluoroprop-2-en-1-amine,-   I-8-Z: (Z)-3-fluoro-2-(4-isopropoxybenzyl)prop-2-en-1-amine,-   I-9-Z: (Z)-3-fluoro-2-(4-(methylthio)benzyl)prop-2-en-1-amine,-   I-10-Z: (Z)-3-fluoro-2-(3-(methylthio)benzyl)prop-2-en-1-amine,-   I-11-Z: (Z)-3-fluoro-2-(4-(methylsulfonyl)benzyl)prop-2-en-1-amine,-   I-12-Z: (Z)-3-fluoro-2-(4-methylbenzyl)prop-2-en-1-amine,-   I-13-Z: (Z)-3-fluoro-2-(3-methylbenzyl)prop-2-en-1-amine,-   I-14-Z: (Z)-3-fluoro-2-(4-isopropylbenzyl)prop-2-en-1-amine,-   I-15-Z: (Z)-2-(4-tert-butylbenzyl)-3-fluoroprop-2-en-1-amine,-   I-16-Z: (Z)-2-(biphenyl-4-ylmethyl)-3-fluoroprop-2-en-1-amine,-   I-17-Z: (Z)-3-fluoro-2-(4-fluorobenzyl)prop-2-en-1-amine,-   I-18-Z: (Z)-3-fluoro-2-(3-(trifluoromethyl)benzyl)prop-2-en-1-amine,-   I-19-Z: (Z)-3-fluoro-2-(3-fluorobenzyl)prop-2-en-1-amine,-   I-20-Z: (Z)-3-fluoro-2-(3-fluoro-4-methylbenzyl)prop-2-en-1-amine,-   I-21-Z: (Z)-3-fluoro-2-(3-fluoro-4-methoxybenzyl)prop-2-en-1-amine,-   I-22-Z: (Z)-3-fluoro-2-(4-fluoro-3-methylbenzyl)prop-2-en-1-amine,-   I-23-Z: (Z)-2-(3-chloro-4-fluorobenzyl)-3-fluoroprop-2-en-1-amine,-   I-24-Z: (Z)-2-(2,5-difluorobenzyl)-3-fluoroprop-2-en-1-amine,-   I-25-Z: (Z)-2-(3-chloro-5-fluorobenzyl)-3-fluoroprop-2-en-1-amine,-   I-26-Z: (Z)-2-(2,4-difluorobenzyl)-3-fluoroprop-2-en-1-amine,-   I-27-Z: (Z)-2-(3,5-dichlorobenzyl)-3-fluoroprop-2-en-1-amine,-   I-28-Z: (Z)-2-(3,4-difluorobenzyl)-3-fluoroprop-2-en-1-amine,-   I-29-Z: (Z)-4-(2-(aminomethyl)-3-fluoroallyl)phenol,-   I-30-Z: (Z)-3-(2-(aminomethyl)-3-fluoroallyl)phenol,-   I-31-Z: (Z)-2-(chloromethylene)-4-(4-fluorophenyl)butan-1-amine,-   I-32-Z: (Z)-2-(chloromethylene)-4-(4-chlorophenyl)butan-1-amine,-   I-33-Z: (Z)-2-(chloromethylene)-4-(4-methoxyphenyl)butan-1-amine,-   I-34-Z: (Z)-2-(chloromethylene)-4-(4-ethoxyphenyl)butan-1-amine,-   I-35-Z:    (Z)-2-(chloromethylene)-4-(4-(trifluoromethyl)phenyl)butan-1-amine,-   I-36-Z: (Z)-4-(4-butoxyphenyl)-2-(chloromethylene)butan-1-amine,-   I-37-Z: (Z)-2-(chloromethylene)-4-m-tolylbutan-1-amine,-   I-38-Z: (Z)-2-(chloromethylene)-4-(3-methoxyphenyl)butan-1-amine,-   I-39-Z: (Z)-2-(chloromethylene)-4-p-tolylbutan-1-amine,-   I-40-Z:    (Z)-2-(chloromethylene)-4-(3-fluoro-5-(trifluoromethyl)phenyl)butan-1-amine,-   I-41-Z: (Z)-2-(chloromethylene)-4-phenylbutan-1-amine,-   I-42-Z: (Z)-2-(chloromethylene)-4-(4-fluorophenyl)butan-1-amine,-   I-43-Z: (Z)-2-(chloromethylene)-4-(4-chlorophenyl)butan-1-amine,-   I-44-Z: (Z)-2-(chloromethylene)-4-(4-methoxyphenyl)butan-1-amine,-   I-45-Z: (Z)-2-(chloromethylene)-4-(4-ethoxyphenyl)butan-1-amine,-   I-46-Z:    (Z)-2-(chloromethylene)-4-(4-(trifluoromethyl)phenyl)butan-1-amine,-   I-47-Z: (Z)-4-(4-butoxyphenyl)-2-(chloromethylene)butan-1-amine,-   I-48-Z: (Z)-2-(chloromethylene)-4-m-tolylbutan-1-amine,-   I-49-Z: (Z)-2-(chloromethylene)-4-(3-methoxyphenyl)butan-1-amine,-   I-50-Z: (Z)-2-(chloromethylene)-4-p-tolylbutan-1-amine,-   I-51-Z:    (Z)-2-(chloromethylene)-4-(3-fluoro-5-(trifluoromethyl)phenyl)butan-1-amine,-   I-52-Z:    (Z)-2-(4-(cyclopropylmethoxy)benzyl)-3-fluoroprop-2-en-1-amine,-   I-53-Z:    (Z)-2-(4-(cyclopropylmethoxy)-3-fluorobenzyl)-3-fluoroprop-2-en-1-amine,-   I-54-Z:    (Z)-3-fluoro-2-(3-fluoro-4-(pentyloxy)benzyl)prop-2-en-1-amine,-   I-55-Z:    (Z)-3-fluoro-2-(2,3,5,6-tetrafluoro-4-methoxybenzyl)prop-2-en-1-amine,-   I-56-Z: (Z)-2-(4-ethoxy-3-fluorobenzyl)-3-fluoroprop-2-en-1-amine,-   I-57-Z:    (Z)-2-(2,3-difluoro-4-methoxybenzyl)-3-fluoroprop-2-en-1-amine,-   I-58-Z:    (Z)-2-(4-(benzyloxy)-3-fluorobenzyl)-3-fluoroprop-2-en-1-amine,-   I-59-Z:    (Z)-3-fluoro-2-(4-fluoro-3-(trifluoromethoxy)benzyl)prop-2-en-1-amine,-   I-60-Z:    (Z)-3-fluoro-2-(4-(2,2,2-trifluoroethoxy)benzyl)prop-2-en-1-amine,-   I-61-Z:    (Z)-2-(3,5-difluoro-4-methoxybenzyl)-3-fluoroprop-2-en-1-amine,-   I-62-Z: (Z)-2-(3-ethoxybenzyl)-3-fluoroprop-2-en-1-amine,-   I-63-Z: (Z)-3-fluoro-2-(3-isopropoxybenzyl)prop-2-en-1-amine,-   I-64-Z:    (Z)-3-fluoro-2-(3-(trifluoromethoxy)benzyl)prop-2-en-1-amine,-   I-65-Z:    (Z)-2-(3-(cyclopropylmethoxy)benzyl)-3-fluoroprop-2-en-1-amine,-   I-66-Z: (Z)-2-(3-(benzyloxy)benzyl)-3-fluoroprop-2-en-1-amine,-   I-67-Z:    (Z)-3-fluoro-2-(2-fluoro-5-(trifluoromethoxy)benzyl)prop-2-en-1-amine,-   I-68-Z:    (Z)-2-(3-chloro-5-(trifluoromethoxy)benzyl)-3-fluoroprop-2-en-1-amine,-   I-69-Z: (Z)-3-fluoro-2-(2,3,5-trifluorobenzyl)prop-2-en-1-amine,-   I-70-Z: (Z)-3-fluoro-2-(3,4,5-trifluorobenzyl)prop-2-en-1-amine,-   I-71-Z: (Z)-3-(2-(aminomethyl)-3-fluoroallyl)benzonitrile,-   I-72-Z: (Z)-2-(4-bromobenzyl)-3-fluoroprop-2-en-1-amine,-   I-73-Z: (Z)-2-(3-bromobenzyl)-3-fluoroprop-2-en-1-amine,-   I-74-Z: (Z)-3-fluoro-2-(pyridin-2-ylmethyl)prop-2-en-1-amine,-   I-75-Z: (Z)-3-fluoro-2-(pyridin-3-ylmethyl)prop-2-en-1-amine,-   I-76-Z: (Z)-3-fluoro-2-(naphthalen-2-ylmethyl)prop-2-en-1-amine,-   I-77-Z: (Z)-2-(benzofuran-2-ylmethyl)-3-fluoroprop-2-en-1-amine,-   I-78-Z: (Z)-2-(benzofuran-3-ylmethyl)-3-fluoroprop-2-en-1-amine,-   I-79-Z: (Z)-3-fluoro-2-(quinolin-3-ylmethyl)prop-2-en-1-amine,-   I-80-Z:    (Z)-2-(benzo[b]thiophen-3-ylmethyl)-3-fluoroprop-2-en-1-amine,-   I-81-Z:    (Z)-2-(benzo[b]thiophen-2-ylmethyl)-3-fluoroprop-2-en-1-amine,-   I-82-E: (E)-3-fluoro-2-((4-fluorophenoxy)methyl)prop-2-en-1-amine,-   I-83-E: (E)-2-((4-chlorophenoxy)methyl)-3-fluoroprop-2-en-1-amine,-   I-84-E: (E)-3-fluoro-2-((4-methoxyphenoxy)methyl)prop-2-en-1-amine,-   I-85-E: (E)-2-((4-ethoxyphenoxy)methyl)-3-fluoroprop-2-en-1-amine,-   I-86-E:    (E)-3-fluoro-2-((4-(trifluoromethyl)phenoxy)methyl)prop-2-en-1-amine,-   I-87-E: (E)-2-((4-butoxyphenoxy)methyl)-3-fluoroprop-2-en-1-amine,-   I-88-E: (E)-3-fluoro-2-(m-tolyloxymethyl)prop-2-en-1-amine,-   I-89-E: (E)-3-fluoro-2-((3-methoxyphenoxy)methyl)prop-2-en-1-amine,-   I-90-E: (E)-3-fluoro-2-(p-tolyloxymethyl)prop-2-en-1-amine,-   I-91-E:    (E)-3-fluoro-2-((3-fluoro-5-(trifluoromethyl)phenoxy)methyl)prop-2-en-1-amine,-   I-92-Z: (Z)-3-fluoro-2-(furan-2-ylmethyl)prop-2-en-1-amine,-   I-93-Z: (Z)-3-fluoro-2-(thiophen-2-ylmethyl)prop-2-en-1-amine,-   I-94-Z:    (Z)-2-((5-chlorothiophen-2-yl)methyl)-3-fluoroprop-2-en-1-amine,-   I-95-Z:    (Z)-3-fluoro-2-((5-methylthiophen-2-yl)methyl)prop-2-en-1-amine,-   I-96-Z: (Z)-3-fluoro-2-(furan-3-ylmethyl)prop-2-en-1-amine,-   I-97-Z: (Z)-3-fluoro-2-(thiophen-3-ylmethyl)prop-2-en-1-amine,-   I-98-Z:    (Z)-2-((5-chlorothiophen-3-yl)methyl)-3-fluoroprop-2-en-1-amine,-   I-99-Z: (Z)-2-(fluoromethylene)-4-(4-fluorophenyl)butan-1-amine,-   I-100-Z: (Z)-2-(fluoromethylene)-4-(3-fluorophenyl)butan-1-amine,-   I-101-Z: (Z)-4-(4-chlorophenyl)-2-(fluoromethylene)butan-1-amine,-   I-102-Z: (Z)-2-(fluoromethylene)-4-(4-methoxyphenyl)butan-1-amine,-   I-103-Z: (Z)-4-(4-ethoxyphenyl)-2-(fluoromethylene)butan-1-amine,-   I-104-Z:    (Z)-2-(fluoromethylene)-4-(4-(trifluoromethyl)phenyl)butan-1-amine,-   I-105-Z: (Z)-4-(4-butoxyphenyl)-2-(fluoromethylene)butan-1-amine,-   I-106-Z: (Z)-2-(fluoromethylene)-4-m-tolylbutan-1-amine,-   I-107-Z: (Z)-2-(fluoromethylene)-4-(3-methoxyphenyl)butan-1-amine,-   I-108-Z: (Z)-2-(fluoromethylene)-4-p-tolylbutan-1-amine,-   I-109-Z:    (Z)-4-(3-fluoro-5-(trifluoromethyl)phenyl)-2-(fluoromethylene)butan-1-amine,    or any stereoisomer, mixture of stereoisomers, prodrug, metabolite,    crystalline form, non-crystalline form, hydrate, solvate, or salt    thereof.

In another embodiment, the present invention relates to any one of thecompounds of general formula I:

-   I-1-E: (E)-3-fluoro-2-(4-methoxybenzyl)prop-2-en-1-amine,-   I-2-E: (E)-2-(4-ethoxybenzyl)-3-fluoroprop-2-en-1-amine,-   I-3-E: (E)-2-(4-chlorobenzyl)-3-fluoroprop-2-en-1-amine,-   I-4-E: (E)-2-(3-chlorobenzyl)-3-fluoroprop-2-en-1-amine,-   I-5-E: (E)-3-fluoro-2-(3-methoxybenzyl)prop-2-en-1-amine,-   I-6-E: (E)-2-(3,4-dimethoxybenzyl)-3-fluoroprop-2-en-1-amine,-   I-7-E: (E)-2-(3,5-dimethoxybenzyl)-3-fluoroprop-2-en-1-amine,-   I-8-E: (E)-3-fluoro-2-(4-isopropoxybenzyl)prop-2-en-1-amine,-   I-9-E: (E)-3-fluoro-2-(4-(methylthio)benzyl)prop-2-en-1-amine,-   I-10-E: (E)-3-fluoro-2-(3-(methylthio)benzyl)prop-2-en-1-amine,-   I-11-E: (E)-3-fluoro-2-(4-(methylsulfonyl)benzyl)prop-2-en-1-amine,-   I-12-E: (E)-3-fluoro-2-(4-methylbenzyl)prop-2-en-1-amine,-   I-13-E: (E)-3-fluoro-2-(3-methylbenzyl)prop-2-en-1-amine,-   I-14-E: (E)-3-fluoro-2-(4-isopropylbenzyl)prop-2-en-1-amine,-   I-15-E: (E)-2-(4-tert-butylbenzyl)-3-fluoroprop-2-en-1-amine,-   I-16-E: (E)-2-(biphenyl-4-ylmethyl)-3-fluoroprop-2-en-1-amine,-   I-17-E: (E)-3-fluoro-2-(4-fluorobenzyl)prop-2-en-1-amine,-   I-18-E: (E)-3-fluoro-2-(3-(trifluoromethyl)benzyl)prop-2-en-1-amine,-   I-19-E: (E)-3-fluoro-2-(3-fluorobenzyl)prop-2-en-1-amine,-   I-20-E: (E)-3-fluoro-2-(3-fluoro-4-methylbenzyl)prop-2-en-1-amine,-   I-21-E: (E)-3-fluoro-2-(3-fluoro-4-methoxybenzyl)prop-2-en-1-amine,-   I-22-E: (E)-3-fluoro-2-(4-fluoro-3-methylbenzyl)prop-2-en-1-amine,-   I-23-E: (E)-2-(3-chloro-4-fluorobenzyl)-3-fluoroprop-2-en-1-amine,-   I-24-E: (E)-2-(2,5-difluorobenzyl)-3-fluoroprop-2-en-1-amine,-   I-25-E: (E)-2-(3-chloro-5-fluorobenzyl)-3-fluoroprop-2-en-1-amine,-   I-26-E: (E)-2-(2,4-difluorobenzyl)-3-fluoroprop-2-en-1-amine,-   I-27-E: (E)-2-(3,5-dichlorobenzyl)-3-fluoroprop-2-en-1-amine,-   I-28-E: (E)-2-(3,4-difluorobenzyl)-3-fluoroprop-2-en-1-amine,-   I-29-E: (E)-4-(2-(aminomethyl)-3-fluoroallyl)phenol,-   I-30-E: (E)-3-(2-(aminomethyl)-3-fluoroallyl)phenol,-   I-31-E: (E)-2-(chloromethylene)-4-(4-fluorophenyl)butan-1-amine,-   I-32-E: (E)-2-(chloromethylene)-4-(4-chlorophenyl)butan-1-amine,-   I-33-E: (E)-2-(chloromethylene)-4-(4-methoxyphenyl)butan-1-amine,-   I-34-E: (E)-2-(chloromethylene)-4-(4-ethoxyphenyl)butan-1-amine,-   I-35-E:    (E)-2-(chloromethylene)-4-(4-(trifluoromethyl)phenyl)butan-1-amine,-   I-36-E: (E)-4-(4-butoxyphenyl)-2-(chloromethylene)butan-1-amine,-   I-37-E: (E)-2-(chloromethylene)-4-m-tolylbutan-1-amine,-   I-38-E: (E)-2-(chloromethylene)-4-(3-methoxyphenyl)butan-1-amine,-   I-39-E: (E)-2-(chloromethylene)-4-p-tolylbutan-1-amine,-   I-40-E:    (E)-2-(chloromethylene)-4-(3-fluoro-5-(trifluoromethyl)phenyl)butan-1-amine,-   I-41-E: (E)-2-(chloromethylene)-4-phenylbutan-1-amine,-   I-42-E: (E)-2-(chloromethylene)-4-(4-fluorophenyl)butan-1-amine,-   I-43-E: (E)-2-(chloromethylene)-4-(4-chlorophenyl)butan-1-amine,-   I-44-E: (E)-2-(chloromethylene)-4-(4-methoxyphenyl)butan-1-amine,-   I-45-E: (E)-2-(chloromethylene)-4-(4-ethoxyphenyl)butan-1-amine,-   I-46-E:    (E)-2-(chloromethylene)-4-(4-(trifluoromethyl)phenyl)butan-1-amine,-   I-47-E: (E)-4-(4-butoxyphenyl)-2-(chloromethylene)butan-1-amine,-   I-48-E: (E)-2-(chloromethylene)-4-m-tolylbutan-1-amine,-   I-49-E: (E)-2-(chloromethylene)-4-(3-methoxyphenyl)butan-1-amine,-   I-50-E: (E)-2-(chloromethylene)-4-p-tolylbutan-1-amine,-   I-51-E:    (E)-2-(chloromethylene)-4-(3-fluoro-5-(trifluoromethyl)phenyl)butan-1-amine,-   I-52-E:    (E)-2-(4-(cyclopropylmethoxy)benzyl)-3-fluoroprop-2-en-1-amine,-   I-53-E:    (E)-2-(4-(cyclopropylmethoxy)-3-fluorobenzyl)-3-fluoroprop-2-en-1-amine,-   I-54-E:    (E)-3-fluoro-2-(3-fluoro-4-(pentyloxy)benzyl)prop-2-en-1-amine,-   I-55-E:    (E)-3-fluoro-2-(2,3,5,6-tetrafluoro-4-methoxybenzyl)prop-2-en-1-amine,-   I-56-E: (E)-2-(4-ethoxy-3-fluorobenzyl)-3-fluoroprop-2-en-1-amine,-   I-57-E:    (E)-2-(2,3-difluoro-4-methoxybenzyl)-3-fluoroprop-2-en-1-amine,-   I-58-E:    (E)-2-(4-(benzyloxy)-3-fluorobenzyl)-3-fluoroprop-2-en-1-amine,-   I-59-E:    (E)-3-fluoro-2-(4-fluoro-3-(trifluoromethoxy)benzyl)prop-2-en-1-amine,-   I-60-E:    (E)-3-fluoro-2-(4-(2,2,2-trifluoroethoxy)benzyl)prop-2-en-1-amine,-   I-61-E:    (E)-2-(3,5-difluoro-4-methoxybenzyl)-3-fluoroprop-2-en-1-amine,-   I-62-E: (E)-2-(3-ethoxybenzyl)-3-fluoroprop-2-en-1-amine,-   I-63-E: (E)-3-fluoro-2-(3-isopropoxybenzyl)prop-2-en-1-amine,-   I-64-E:    (E)-3-fluoro-2-(3-(trifluoromethoxy)benzyl)prop-2-en-1-amine,-   I-65-E:    (E)-2-(3-(cyclopropylmethoxy)benzyl)-3-fluoroprop-2-en-1-amine,-   I-66-E: (E)-2-(3-(benzyloxy)benzyl)-3-fluoroprop-2-en-1-amine,-   I-67-E:    (E)-3-fluoro-2-(2-fluoro-5-(trifluoromethoxy)benzyl)prop-2-en-1-amine,-   I-68-E:    (E)-2-(3-chloro-5-(trifluoromethoxy)benzyl)-3-fluoroprop-2-en-1-amine,-   I-69-E: (E)-3-fluoro-2-(2,3,5-trifluorobenzyl)prop-2-en-1-amine,-   I-70-E: (E)-3-fluoro-2-(3,4,5-trifluorobenzyl)prop-2-en-1-amine,-   I-71-E: (E)-3-(2-(aminomethyl)-3-fluoroallyl)benzonitrile,-   I-72-E: (E)-2-(4-bromobenzyl)-3-fluoroprop-2-en-1-amine,-   I-73-E: (E)-2-(3-bromobenzyl)-3-fluoroprop-2-en-1-amine,-   I-74-E: (E)-3-fluoro-2-(pyridin-2-ylmethyl)prop-2-en-1-amine,-   I-75-E: (E)-3-fluoro-2-(pyridin-3-ylmethyl)prop-2-en-1-amine,-   I-76-E: (E)-3-fluoro-2-(naphthalen-2-ylmethyl)prop-2-en-1-amine,-   I-77-E: (E)-2-(benzofuran-2-ylmethyl)-3-fluoroprop-2-en-1-amine,-   I-78-E: (E)-2-(benzofuran-3-ylmethyl)-3-fluoroprop-2-en-1-amine,-   I-79-E: (E)-3-fluoro-2-(quinolin-3-ylmethyl)prop-2-en-1-amine,-   I-80-E:    (E)-2-(benzo[b]thiophen-3-ylmethyl)-3-fluoroprop-2-en-1-amine,-   I-81-E:    (E)-2-(benzo[b]thiophen-2-ylmethyl)-3-fluoroprop-2-en-1-amine,-   I-82-Z: (Z)-3-fluoro-2-((4-fluorophenoxy)methyl)prop-2-en-1-amine,-   I-83-Z: (Z)-2-((4-chlorophenoxy)methyl)-3-fluoroprop-2-en-1-amine,-   I-84-Z: (Z)-3-fluoro-2-((4-methoxyphenoxy)methyl)prop-2-en-1-amine,-   I-85-Z: (Z)-2-((4-ethoxyphenoxy)methyl)-3-fluoroprop-2-en-1-amine,-   I-86-Z:    (Z)-3-fluoro-2-((4-(trifluoromethyl)phenoxy)methyl)prop-2-en-1-amine,-   I-87-Z: (Z)-2-((4-butoxyphenoxy)methyl)-3-fluoroprop-2-en-1-amine,-   I-88-Z: (Z)-3-fluoro-2-(m-tolyloxymethyl)prop-2-en-1-amine,-   I-89-Z: (Z)-3-fluoro-2-((3-methoxyphenoxy)methyl)prop-2-en-1-amine,-   I-90-Z: (Z)-3-fluoro-2-(p-tolyloxymethyl)prop-2-en-1-amine,-   I-91-Z:    (Z)-3-fluoro-2-((3-fluoro-5-(trifluoromethyl)phenoxy)methyl)prop-2-en-1-amine,-   I-92-E: (E)-3-fluoro-2-(furan-2-ylmethyl)prop-2-en-1-amine,-   I-93-E: (E)-3-fluoro-2-(thiophen-2-ylmethyl)prop-2-en-1-amine,-   I-94-E:    (E)-2-((5-chlorothiophen-2-yl)methyl)-3-fluoroprop-2-en-1-amine,-   I-95-E:    (E)-3-fluoro-2-((5-methylthiophen-2-yl)methyl)prop-2-en-1-amine,-   I-96-E: (E)-3-fluoro-2-(furan-3-ylmethyl)prop-2-en-1-amine,-   I-97-E: (E)-3-fluoro-2-(thiophen-3-ylmethyl)prop-2-en-1-amine,-   I-98-E:    (E)-2-((5-chlorothiophen-3-yl)methyl)-3-fluoroprop-2-en-1-amine,-   I-99-E: (E)-2-(fluoromethylene)-4-(4-fluorophenyl)butan-1-amine,-   I-100-E: (E)-2-(fluoromethylene)-4-(3-fluorophenyl)butan-1-amine,-   I-101-E: (E)-4-(4-chlorophenyl)-2-(fluoromethylene)butan-1-amine,-   I-102-E: (E)-2-(fluoromethylene)-4-(4-methoxyphenyl)butan-1-amine,-   I-103-E: (E)-4-(4-ethoxyphenyl)-2-(fluoromethylene)butan-1-amine,-   I-104-E:    (E)-2-(fluoromethylene)-4-(4-(trifluoromethyl)phenyl)butan-1-amine,-   I-105-E: (E)-4-(4-butoxyphenyl)-2-(fluoromethylene)butan-1-amine,-   I-106-E: (E)-2-(fluoromethylene)-4-m-tolylbutan-1-amine,-   I-107-E: (E)-2-(fluoromethylene)-4-(3-methoxyphenyl)butan-1-amine,-   I-108-E: (E)-2-(fluoromethylene)-4-p-tolylbutan-1-amine,-   I-109-E:    (E)-4-(3-fluoro-5-(trifluoromethyl)phenyl)-2-(fluoromethylene)butan-1-amine,    or any stereoisomer, mixture of stereoisomers, prodrug, metabolite,    crystalline form, non-crystalline form, hydrate, solvate, or salt    thereof.

In another embodiment, the present invention relates to methods of usingone or more of the compounds of formula I-1, I-2, I-3, I-4, I-5, I-6,I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-15, I-16, I-17, I-18,I-19, I-20, I-21, I-22, I-23, I-24, I-25, I-26, I-27, I-28, I-29, I-30,I-31, I-32, I-33, I-34, I-35, I-36, I-37, I-38, I-39, I-40, I-41, I-42,I-43, I-44, I-45, I-46, I-47, I-48, I-49, I-50, I-51, I-52, I-53, I-54,I-55, I-56, I-57, I-58, I-59, I-60, I-61, I-62, I-63, I-64, I-65, I-66,I-67, I-68, I-69, I-70, I-71, I-72, I-73, I-74, I-75, I-76, I-77, I-78,I-79, I-80, I-81, I-82, I-83, I-84, I-85, I-86, I-87, I-88, I-89, I-90,I-91, I-92, I-93, I-94, I-95, I-96, I-97, I-98, I-99, I-100, I-101,I-102, I-103, I-104, I-105, I-106, I-107, I-108, I-109 to inhibit SSAOenzyme activity (whether the enzyme activity is due either to solubleSSAO enzyme or membrane-bound VAP-1 protein, or due to both) and/orinhibit binding to VAP-1 protein. The compound(s) can be used for amethod of inhibiting SSAO activity or inhibiting binding to VAP-1 invitro, by supplying the compound(s) to the in vitro environment in anamount sufficient to inhibit SSAO activity or inhibit binding to VAP-1.The compound(s) can also be used for a method of inhibiting SSAOactivity or inhibiting binding to VAP-1 in vivo, that is, in a livingorganism, such as a vertebrate, mammal, or human, by administering thecompound(s) to the organism in an amount sufficient to inhibit SSAOactivity or inhibit binding to VAP-1. In another embodiment, the presentinvention relates to methods of using one or more compounds of formulaI-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13,I-14, I-15, I-16, I-17, I-18, I-19, I-20, I-21, I-22, I-23, I-24, I-25,I-26, I-27, I-28, I-29, I-30, I-31, I-32, I-33, I-34, I-35, I-36, I-37,I-38, I-39, I-40, I-41, I-42, I-43, I-44, I-45, I-46, I-47, I-48, I-49,I-50, I-51, I-52, I-53, I-54, I-55, I-56, I-57, I-58, I-59, I-60, I-61,I-62, I-63, I-64, I-65, I-66, I-67, I-68, I-69, I-70, I-71, I-72, I-73,I-74, I-75, I-76, I-77, I-78, I-79, I-80, I-81, I-82, I-83, I-84, I-85,I-86, I-87, I-88, I-89, I-90, I-91, I-92, I-93, I-94, I-95, I-96, I-97,I-98, I-99, I-100, I-101, I-102, I-103, I-104, I-105, I-106, I-107,I-108, I-109 to treat or prevent inflammation or immune disorders. Inanother embodiment, the present invention relates to methods of usingone or more compounds of formula I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8,I-9, I-10, I-11, I-12, I-13, I-14, I-15, I-16, I-17, I-18, I-19, I-20,I-21, I-22, I-23, I-24, I-25, I-26, I-27, I-28, I-29, I-30, I-31, I-32,I-33, I-34, I-35, I-36, I-37, I-38, I-39, I-40, I-41, I-42, I-43, I-44,I-45, I-46, I-47, I-48, I-49, I-50, I-51, I-52, I-53, I-54, I-55, I-56,I-57, I-58, I-59, I-60, I-61, I-62, I-63, I-64, I-65, I-66, I-67, I-68,I-69, I-70, I-71, I-72, I-73, I-74, I-75, I-76, I-77, I-78, I-79, I-80,I-81, I-82, I-83, I-84, I-85, I-86, I-87, I-88, I-89, I-90, I-91, I-92,I-93, I-94, I-95, I-96, I-97, I-98, I-99, I-100, I-101, I-102, I-103,I-104, I-105, I-106, I-107, I-108, I-109 to suppress or reduceinflammation, or to suppress or reduce an inflammatory response. Inanother embodiment, the present invention relates to methods of treatingor preventing inflammation, by administering on or more compoundsdescribed in formula I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10,I-11, I-12, I-13, I-14, I-15, I-16, I-17, I-18, I-19, I-20, I-21, I-22,I-23, I-24, I-25, I-26, I-27, I-28, I-29, I-30, I-31, I-32, I-33, I-34,I-35, I-36, I-37, I-38, I-39, I-40, I-41, I-42, I-43, I-44, I-45, I-46,I-47, I-48, I-49, I-50, I-51, I-52, I-53, I-54, I-55, I-56, I-57, I-58,I-59, I-60, I-61, I-62, I-63, I-64, I-65, I-66, I-67, I-68, I-69, I-70,I-71, I-72, I-73, I-74, I-75, I-76, I-77, I-78, I-79, I-80, I-81, I-82,I-83, I-84, I-85, I-86, I-87, I-88, I-89, I-90, I-91, I-92, I-93, I-94,I-95, I-96, I-97, I-98, I-99, I-100, I-101, I-102, I-103, I-104, I-105,I-106, I-107, I-108, I-109 in a therapeutically effective amount, or inan amount sufficient to treat or prevent inflammation. In anotherembodiment, the present invention relates to methods of treating orpreventing immune or autoimmune disorders, by administering one or morecompounds of formula I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10,I-11, I-12, I-13, I-14, I-15, I-16, I-17, I-18, I-19, I-20, I-21, I-22,I-23, I-24, I-25, I-26, I-27, I-28, I-29, I-30, I-31, I-32, I-33, I-34,I-35, I-36, I-37, I-38, I-39, I-40, I-41, I-42, I-43, I-44, I-45, I-46,I-47, I-48, I-49, I-50, I-51, I-52, I-53, I-54, I-55, I-56, I-57, I-58,I-59, I-60, I-61, I-62, I-63, I-64, I-65, I-66, I-67, I-68, I-69, I-70,I-71, I-72, I-73, I-74, I-75, I-76, I-77, I-78, I-79, I-80, I-81, I-82,I-83, I-84, I-85, I-86, I-87, I-88, I-89, I-90, I-91, I-92, I-93, I-94,I-95, I-96, I-97, I-98, I-99, I-100, I-101, I-102, I-103, I-104, I-105,I-106, I-107, I-108, I-109 in a therapeutically effective amount, or inan amount sufficient to treat or prevent the immune or autoimmunedisorder.

In another embodiment, the invention relates to compounds of formula II:

wherein Y is a phenyl, naphthyl, or pyridyl group optionally substitutedwith one or more groups of the form R₁, wherein each R₁ is independentlyselected from H, C₁-C₈ alkyl, C₃-C₈ cycloalkyl, —O—C₁-C₈ alkyl, —O—C₃-C₈cycloalkyl, —C₆-C₁₀ aryl, —O—C₁-C₄ alkyl-C₆-C₁₀ aryl, —S—C₁-C₈ alkyl,—CF₃, —OCF₃, F, Cl, Br, I, —NO₂, —OH, —NR₅R₆, —NHR₇, and —S(O₂)—(C₁-C₈alkyl); R₂ is selected from H, F, Cl, C₁-C₄ alkyl, and CF₃; R₃ and R₄are independently selected from H, —C₁-C₈ alkyl, —C₁-C₄ alkyl-C₆-C₁₀aryl, or R₃ and R₄ together with the nitrogen to which they are attachedform a nitrogen-containing ring (including, but not limited to,morpholino, piperidino, and piperazino); R₅ and R₆ are independentlyselected from H, —C₁-C₈ alkyl, —C₁-C₄ alkyl-C₆-C₁₀ aryl, or R₅ and R₆together with the nitrogen to which they are attached form anitrogen-containing ring (including, but not limited to, morpholino,piperidino, and piperazino); R₇ is selected from —C(═O)—(C₁-C₈ alkyl)and —C(═O)—(C₆-C₁₀ aryl); R₈ is selected from H, C₁-C₈ alkyl, C₆-C₁₀aryl, —C₁-C₄ alkyl-C₆-C₁₀ aryl, and —CF₃; X is —CH₂—, —O—, or —S—; n is0, 1, 2, or 3; and p is 0, 1, 2, or 3; and any stereoisomer, mixture ofstereoisomers, prodrug, metabolite, crystalline form, non-crystallineform, hydrate, solvate, or salt thereof. In another embodiment, X is CH₂and n is 0 or 1. In another embodiment, X is CH₂ and n is 0. In anotherembodiment, X is CH₂ and n is 1. In another embodiment, X is O or S andn is 1. In another embodiment, R₁ is selected from C₁-C₄ alkyl, —S—C₁-C₄alkyl, or —O—C₁-C₄ alkyl. In another embodiment, Y is phenyl, optionallysubstituted with one or more R₁ substituents. In another embodiment, R₃and R₄ are both H. In another embodiment, the compounds of formula IIare in the E configuration of the double bond; those compounds aredesignated as compounds of formula II-E. In another embodiment, thecompounds of formula II are in the Z configuration of the double bond;those compounds are designated as compounds of formula II-Z.

In another embodiment, the invention relates to compounds of formulaII-A:

wherein each R₁ is independently selected from H, C₁-C₈ alkyl, C₃-C₈cycloalkyl, —O—C₁-C₈ alkyl, —O—C₃-C₈ cycloalkyl, —C₆-C₁₀ aryl, —O—C₁-C₄alkyl-C₆-C₁₀ aryl, —S—C₁-C₈ alkyl, —CF₃, —OCF₃, F, Cl, Br, I, —NO₂, —OH,—NR₅R₆, —NHR₇, and —S(O₂)—(C₁-C₈ alkyl); R₂ is selected from H, F, Cl,C₁-C₄ alkyl, and CF₃; R₃ and R₄ are independently selected from H,—C₁-C₈ alkyl, —C₁-C₄ alkyl-C₆-C₁₀ aryl, or R₃ and R₄ together with thenitrogen to which they are attached form a nitrogen-containing ring(including, but not limited to, morpholino, piperidino, and piperazino);R₅ and R₆ are independently selected from H, —C₁-C₈ alkyl, —C₁-C₄alkyl-C₆-C₁₀ aryl, or R₅ and R₆ together with the nitrogen to which theyare attached form a nitrogen-containing ring (including, but not limitedto, morpholino, piperidino, and piperazino); R₇ is selected from—C(═O)—(C₁-C₈ alkyl) and —C(═O)—(C₆-C₁₀ aryl); R₈ is selected from H,C₁-C₈ alkyl, C₆-C₁₀ aryl, —C₁-C₄ alkyl-C₆-C₁₀ aryl, and —CF₃; X is—CH₂—, —O—, or —S—; n is 0, 1, 2, or 3; and p is 0, 1, 2, or 3; and anystereoisomer, mixture of stereoisomers, prodrug, metabolite, crystallineform, non-crystalline form, hydrate, solvate, or salt thereof. Inanother embodiment, X is CH₂ and n is 0 or 1. In another embodiment, Xis CH₂ and n is 0. In another embodiment, X is CH₂ and n is 1. Inanother embodiment, X is O or S and n is 1. In another embodiment, R₁ isselected from C₁-C₄ alkyl, —S—C₁-C₄ alkyl, or —O—C₁-C₄ alkyl. In anotherembodiment, R₃ and R₄ are both H. In another embodiment, the compoundsof formula II-A are in the E configuration of the double bond; thosecompounds are designated as compounds of formula II-A-E. In anotherembodiment, the compounds of formula II-A are in the Z configuration ofthe double bond; those compounds are designated as compounds of formulaII-A-Z.

In one embodiment of the compounds of formula II, II-E, II-Z, II-A,II-A-Z, or II-A-E, n is 0. In another embodiment, R₁ is selected fromC₁-C₄ alkyl or —O—C₁-C₄ alkyl. In another embodiment, n is 0 and X is—CH₂—. In another embodiment, n is 0, X is —CH₂—, and R₃ and R₄ are H.In another embodiment, n is 0, X is —CH₂—, R₃ and R₄ are H, and each R₁is independently selected from H, C₁-C₄ alkyl, C₃-C₈ cycloalkyl,—O—C₁-C₄ alkyl, —S—C₁-C₄ alkyl, CF₃, —O—CF₃, F, and Cl. In anotherembodiment, n is 0, X is —CH₂—, R₃ and R₄ are H, each R₁ isindependently selected from H, C₁-C₄ alkyl, C₃-C₈ cycloalkyl, —O—C₁-C₄alkyl, —S—C₁-C₄ alkyl, CF₃, —O—CF₃, F, and Cl, and p is 1 or 2.

In another embodiment, the invention relates to compounds of formulaII-B:

wherein each R₁ is independently selected from H, C₁-C₈ alkyl, C₃-C₈cycloalkyl, —O—C₁-C₈ alkyl, —O—C₃-C₈ cycloalkyl, —C₆-C₁₀ aryl, —O—C₁-C₄alkyl-C₆-C₁₀ aryl, —S—C₁-C₈ alkyl, —CF₃, —OCF₃, F, Cl, Br, I, —NO₂, —OH,—NR₅R₆, —NHR₇, and —S(O₂)—(C₁-C₈ alkyl); R₂ is selected from H, F, C₁-C₄alkyl, and CF₃; R₅ and R₆ are independently selected from H, —C₁-C₈alkyl, —C₁-C₄ alkyl-C₆-C₁₀ aryl, or R₅ and R₆ together with the nitrogento which they are attached form a nitrogen-containing ring (including,but not limited to, morpholino, piperidino, and piperazino); R₇ isselected from —C(═O)—(C₁-C₈ alkyl) and —C(═O)—(C₆-C₁₀ aryl); X is —CH₂—,—O—, or —S—; n is 0, 1, 2, or 3; and p is 0, 1, 2, or 3; and anystereoisomer, mixture of stereoisomers, prodrug, metabolite, crystallineform, non-crystalline form, hydrate, solvate, or salt thereof. Inanother embodiment, the compounds of formula II-B are in the Econfiguration of the double bond; those compounds are designated ascompounds of formula II-B-E. In another embodiment, the compounds offormula II-B are in the Z configuration of the double bond; thosecompounds are designated as compounds of formula II-B-Z.

In one embodiment of the compounds of formula II-B, II-B-Z, or II-B-E, nis 0. In another embodiment, R₁ is selected from C₁-C₄ alkyl, —S—C₁-C₄alkyl, or —O—C₁-C₄ alkyl. In another embodiment, n is 0 and X is —CH₂—.In another embodiment, n is 0, X is —CH₂—, and R₂ is F. In anotherembodiment, n is 0, X is —CH₂—, R₂ is F, and each R₁ is independentlyselected from H, C₁-C₄ alkyl, C₃-C₈ cycloalkyl, —O—C₁-C₄ alkyl, —S—C₁-C₄alkyl, CF₃, —O—CF₃, F, and Cl. In another embodiment, n is 0, X is—CH₂—, R₂ is F, each R₁ is independently selected from H, C₁-C₄ alkyl,C₃-C₈ cycloalkyl, —O—C₁-C₄ alkyl, —S—C₁-C₄ alkyl, —CF₃, —O—CF₃, F, andCl, and p is 1 or 2. In another embodiment, n is 0, X is —CH₂—, R₂ is F,each R₁ is independently selected from H, C₁-C₄ alkyl, C₃-C₈ cycloalkyl,—O—C₁-C₄ alkyl, —S—C₁-C₄ alkyl, CF₃, —O—CF₃, F, and Cl, and p is 1. Inanother embodiment, n is 0, X is —CH₂—, R₂ is F, each R₁ isindependently selected from H, C₁-C₄ alkyl, C₃-C₈ cycloalkyl, —O—C₁-C₄alkyl, —S—C₁-C₄ alkyl, CF₃, —O—CF₃, F, and Cl, and p is 2. In anotherembodiment, n is 0, X is —CH₂—, R₂ is F, each R₁ is independentlyselected from CF₃, —O—CF₃, —S—CF₃, —O—CH₃, F, and Cl, and p is 1. Inanother embodiment, n is 0, X is —CH₂—, R₂ is F, each R₁ isindependently selected from CF₃, —O—CF₃, —S—CF₃, —O—CH₃, F, and Cl, andp is 2.

In another embodiment, the present invention relates to any one of thecompounds of general formula II of the formula:

or any stereoisomer, mixture of stereoisomers, prodrug, metabolite,crystalline form, non-crystalline form, hydrate, solvate, or saltthereof.

In another embodiment, the present invention relates to any one of thecompounds of general formula I:

-   II-1-E:    (E)-2-fluoro-4-(3-fluoro-5-(trifluoromethyl)phenyl)but-2-en-1-amine,-   II-2-E: (E)-2-fluoro-4-(3-(trifluoromethyl)phenyl)but-2-en-1-amine,-   II-3-E: (E)-2-fluoro-4-(4-methoxyphenyl)but-2-en-1-amine,-   II-4-E:    (E)-2-fluoro-4-(4-methoxy-3-(trifluoromethyl)phenyl)but-2-en-1-amine,-   II-5-E: (E)-2-fluoro-4-(4-fluorophenyl)but-2-en-1-amine,-   II-6-E: (E)-2-fluoro-4-m-tolylbut-2-en-1-amine,-   II-7-E: (E)-2-fluoro-4-(3-fluorophenyl)but-2-en-1-amine,-   II-8-E: (E)-2-fluoro-4-(3-methoxyphenyl)but-2-en-1-amine,-   II-9-E: (E)-2-fluoro-4-phenylbut-2-en-1-amine,-   II-10-E:    (E)-2-fluoro-4-(3-(trifluoromethoxy)phenyl)but-2-en-1-amine,-   II-11-E: (E)-3-(4-amino-3-fluorobut-2-enyl)-N,N-dimethylbenzenamine,-   II-12-E:    (E)-4-(3,5-bis(trifluoromethyl)phenyl)-2-fluorobut-2-en-1-amine,-   II-13-E: (E)-2-fluoro-4-(3-(methylthio)phenyl)but-2-en-1-amine,-   II-14-E: (E)-2-fluoro-4-(3-(methylsulfonyl)phenyl)but-2-en-1-amine,-   II-15-E:    (E)-2-fluoro-4-(3-(trifluoromethylthio)phenyl)but-2-en-1-amine,-   II-16-E: (E)-2-fluoro-4-(3-(methoxymethyl)phenyl)but-2-en-1-amine,-   II-17-E: (E)-2-fluoro-4-(2-methoxyphenyl)but-2-en-1-amine,-   II-18-E: (E)-2-fluoro-4-(3-methoxyphenyl)-3-methylbut-2-en-1-amine,-   II-19-E: (E)-2-fluoro-4-(3-methoxyphenoxy)but-2-en-1-amine,-   II-20-E: (E)-2-fluoro-4-(3-methoxyphenylthio)but-2-en-1-amine,-   II-21-E:    (E)-2-fluoro-4-(3-(trifluoromethyl)phenoxy)but-2-en-1-amine,-   II-22-E: (E)-2-fluoro-4-(pyridin-3-yloxy)but-2-en-1-amine,-   II-23-E: (E)-2-fluoro-5-(3-methoxyphenyl)pent-2-en-1-amine,    or any stereoisomer, mixture of stereoisomers, prodrug, metabolite,    crystalline form, non-crystalline form, hydrate, solvate, or salt    thereof.

In another embodiment, the present invention relates to any one of thecompounds of general formula I:

-   II-1-E:    (Z)-2-fluoro-4-(3-fluoro-5-(trifluoromethyl)phenyl)but-2-en-1-amine,-   II-2-E: (Z)-2-fluoro-4-(3-(trifluoromethyl)phenyl)but-2-en-1-amine,-   II-3-Z: (Z)-2-fluoro-4-(4-methoxyphenyl)but-2-en-1-amine,-   II-4-Z:    (Z)-2-fluoro-4-(4-methoxy-3-(trifluoromethyl)phenyl)but-2-en-1-amine,-   II-5-Z: (Z)-2-fluoro-4-(4-fluorophenyl)but-2-en-1-amine,-   II-6-Z: (Z)-2-fluoro-4-m-tolylbut-2-en-1-amine,-   II-7-Z: (Z)-2-fluoro-4-(3-fluorophenyl)but-2-en-1-amine,-   II-8-Z: (Z)-2-fluoro-4-(3-methoxyphenyl)but-2-en-1-amine,-   II-9-Z: (Z)-2-fluoro-4-phenylbut-2-en-1-amine,-   II-10-Z:    (Z)-2-fluoro-4-(3-(trifluoromethoxy)phenyl)but-2-en-1-amine,-   II-11-Z: (Z)-3-(4-amino-3-fluorobut-2-enyl)-N,N-dimethylbenzenamine,-   II-12-Z:    (Z)-4-(3,5-bis(trifluoromethyl)phenyl)-2-fluorobut-2-en-1-amine,-   II-13-Z: (Z)-2-fluoro-4-(3-(methylthio)phenyl)but-2-en-1-amine,-   II-14-Z: (Z)-2-fluoro-4-(3-(methylsulfonyl)phenyl)but-2-en-1-amine,-   II-15-Z:    (Z)-2-fluoro-4-(3-(trifluoromethylthio)phenyl)but-2-en-1-amine,-   II-16-Z: (Z)-2-fluoro-4-(3-(methoxymethyl)phenyl)but-2-en-1-amine,-   II-17-Z: (Z)-2-fluoro-4-(2-methoxyphenyl)but-2-en-1-amine,-   II-18-Z: (Z)-2-fluoro-4-(3-methoxyphenyl)-3-methylbut-2-en-1-amine,-   II-19-Z: (Z)-2-fluoro-4-(3-methoxyphenoxy)but-2-en-1-amine,-   II-20-Z: (Z)-2-fluoro-4-(3-methoxyphenylthio)but-2-en-1-amine,-   II-21-Z:    (Z)-2-fluoro-4-(3-(trifluoromethyl)phenoxy)but-2-en-1-amine,-   II-22-Z: (Z)-2-fluoro-4-(pyridin-3-yloxy)but-2-en-1-amine,-   II-23-Z: (Z)-2-fluoro-5-(3-methoxyphenyl)pent-2-en-1-amine,    or any stereoisomer, mixture of stereoisomers, prodrug, metabolite,    crystalline form, non-crystalline form, hydrate, solvate, or salt    thereof.

In another embodiment, the present invention relates to methods of usingone or more compounds of formula II-1, II-2, II-3, II-4, II-5, II-6,II-7, II-8, II-9, II-10, II-11, II-12, II-13, II-14, II-15, II-16,II-17, II-18, II-19, II-20, II-21, II-22, or II-23 to inhibit SSAOenzyme activity (whether the enzyme activity is due either to solubleSSAO enzyme or membrane-bound VAP 1 protein, or due to both) and/orinhibit binding to VAP-1 protein. The compound(s) can be used for amethod of inhibiting SSAO activity or inhibiting binding to VAP-1 invitro, by supplying the compound(s) to the in vitro environment in anamount sufficient to inhibit SSAO activity or inhibit binding to VAP-1.The compound(s) can also be used for a method of inhibiting SSAOactivity or inhibiting binding to VAP-1 in vivo, that is, in a livingorganism, such as a vertebrate, mammal, or human, by administering thecompound(s) to the organism in an amount sufficient to inhibit SSAOactivity or inhibit binding to VAP-1. In another embodiment, the presentinvention relates to methods of using one or more compounds of formulaII-1, II-2, II-3, II-4, II-5, II-6, II-7, II-8, II-9, II-10, II-11,II-12, II-13, II-14, II-15, II-16, II-17, II-18, II-19, II-20, II-21,II-22, or II-23 to treat or prevent inflammation or immune disorders. Inanother embodiment, the present invention relates to methods of usingone or more compounds of formula II-1, II-2, II-3, II-4, II-5, II-6,II-7, II-8, II-9, II-10, II-11, II-12, II-13, II-14, II-15, II-16,II-17, II-18, II-19, II-20, II-21, II-22, or I-23 to suppress or reduceinflammation, or to suppress or reduce an inflammatory response. Inanother embodiment, the present invention relates to methods of treatingor preventing inflammation, by administering one or more compounds offormula II-1, II-2, II-3, II-4, II-5, II-6, II-7, II-8, II-9, II-10,II-11, II-12, II-13, II-14, II-15, II-16, II-17, II-18, II-19, II-20,II-21, II-22, or II-23 in a therapeutically effective amount, or in anamount sufficient to treat or prevent inflammation. In anotherembodiment, the present invention relates to methods of treating orpreventing immune or autoimmune disorders, by administering one or morecompounds of formula II-1, II-2, II-3, II-4, II-5, II-6, II-7, II-8,II-9, II-10, II-11, II-12, II-13, II-14, II-15, II-16, II-17, II-18,II-19, II-20, II-21, II-22, or II-23 in a therapeutically effectiveamount, or in an amount sufficient to treat or prevent the immune orautoimmune disorder.

In another embodiment, the present invention relates to compounds of theformula III:

wherein Y is aryl, heteroaryl, or —C₁-C₈ alkyl, optionally substitutedwith one or more groups from R₁, wherein R₁ is independently selectedfrom —H, —C₁-C₈ alkyl, —C₃-C₈ cycloalkyl, —O—C₁-C₈ alkyl, —C₁-C₈alkyl-O—C₁-C₈ alkyl, —O—C₃-C₈ cycloalkyl, —O—C₁-C₈ alkyl-C₃-C₈cycloalkyl, —C₆-C₁₀ aryl, —O—C₁-C₄ alkyl-C₆-C₁₀ aryl, —S—C₁-C₈ alkyl,—CF₃, —S—CF₃, —OCF₃, —OCH₂CF₃, —CN, —F, —Cl, —Br, —I, —NO₂, —OH, —NHR₇,—NR₅R₆, and —S(O₂)—(C₁-C₈ alkyl); R₇ is selected from —C(═O)—(C₁-C₈alkyl) and —C(═O)—(C₆-C₁₀ aryl); R₅ and R₆ are independently selectedfrom —H, —C₁-C₈ alkyl, —C₁-C₄ alkyl-C₆-C₁₀ aryl, or R₅ and R₆ togetherwith the nitrogen to which they are attached form a nitrogen-containingring; X is selected from —CH₂—, —O—, and —S—; n is selected from 0, 1,2, and 3; and Q is H or a suitable protecting group; and anystereoisomer, mixture of stereoisomers, prodrug, metabolite, crystallineform, non-crystalline form, hydrate, solvate, or salt thereof. Inanother embodiment, the compounds of formula III have the provisos thatY is not 4-pyridyl. In another embodiment, the compounds of formula IIIhave the provisos that R₁ is not phenyl. The compounds of formula IIIwith a proviso are designated as compounds of formula III-P. In anotherembodiment, Q is a H. In another embodiment, Q is a Boc protectinggroup. In another embodiment, X is —CH₂—; and n is 0. In anotherembodiment, X is —CH₂—; and n is 0. In another embodiment, X is —O— or—S—; and n is 1 or 2.

In another embodiment, the present invention relates to compounds of theformula III-A:

wherein Y is aryl or heteroaryl, optionally substituted with one or moregroups from R₁, wherein R₁ is independently selected from —H, —C₁-C₈alkyl, —C₃-C₈ cycloalkyl, —O—C₁-C₈ alkyl, —C₁-C₈ alkyl-O—C₁-C₈ alkyl,—O—C₃-C₈ cycloalkyl, —O—C₁-C₈ alkyl-C₃-C₈ cycloalkyl, —C₆-C₁₀ aryl,—O—C₁-C₄ alkyl-C₆-C₁₀ aryl, —S—C₁-C₈ alkyl, —CF₃, —OCF₃, —S—CF₃,—OCH₂CF₃, —CN, —F, —Cl, —Br, —I, —NO₂, —OH, —NHR₇, —NR₅R₆, and—S(O₂)—(C₁-C₈ alkyl); R₇ is selected from —C(═O)—(C₁-C₈ alkyl) and—C(═O)—(C₆-C₁₀ aryl); R₅ and R₆ are independently selected from —H,—C₁-C₈ alkyl, —C₁-C₄ alkyl-C₆-C₁₀ aryl, or R₅ and R₆ together with thenitrogen to which they are attached form a nitrogen-containing ring; X—CH₂—; n is selected from 0, 1, and 2; and PG is a suitable protectinggroup; any stereoisomer, mixture of stereoisomers, prodrug, metabolite,crystalline form, non-crystalline form, hydrate, solvate, or saltthereof. In another embodiment, the compounds of formula III-A have theprovisos that Y is not 4-pyridyl. In another embodiment, the compoundsof formula III-A have the provisos that R₁ is not phenyl. The compoundsof formula III-A with a proviso are designated as compounds of formulaII-AP. In another embodiment, X is —CH₂—; and n is 0. In anotherembodiment, X is —CH₂—; and n is 0. In another embodiment, X is —O— or—S—; and n is 1 or 2.

In another embodiment, the present invention relates to any one of thecompounds of general formula III of the formula:

or any stereoisomer, mixture of stereoisomers, prodrug, metabolite,crystalline form, non-crystalline form, hydrate, solvate, or saltthereof.

In another embodiment, the present invention relates to compounds of theformula IV:

wherein Y is aryl, heteroaryl, or —C₁-C₈ alkyl, optionally substitutedwith one, two, three, four, or five groups from R₁, wherein R₁ isindependently selected from —H, —C₁-C₈ alkyl, —C₃-C₈ cycloalkyl,—O—C₁-C₈ alkyl, —C₁-C₈ alkyl-O—C₁-C₈ alkyl, —O—C₃-C₈ cycloalkyl,—O—C₁-C₈ alkyl-C₃-C₈ cycloalkyl, —C₆-C₁₀ aryl, —O—C₁-C₄ alkyl-C₆-C₁₀aryl, —S—C₁-C₈ alkyl, —CF₃, —S—CF₃, —OCF₃, —OCH₂CF₃, —CN, —F, —Cl, —Br,—I, —NO₂, —OH, —NHR₇, —NR₅R₆, and —S(O₂)—(C₁-C₈ alkyl); R₇ is selectedfrom —C(═O)—(C₁-C₈ alkyl) and —C(═O)—(C₆-C₁₀ aryl); R₅ and R₆ areindependently selected from —H, —C₁-C₈ alkyl, —C₁-C₄ alkyl-C₆-C₁₀ aryl,or R₅ and R₆ together with the nitrogen to which they are attached forma nitrogen-containing ring; X is selected from —CH₂—, —O—, and —S—; andn is selected from 0, 1, 2, and 3; and any stereoisomer, mixture ofstereoisomers, prodrug, metabolite, crystalline form, non-crystallineform, hydrate, solvate, or salt thereof.

In another embodiment, formula IV is subject to the proviso that when Yis phenyl, R₃ and R₄ are both H, X is CH₂, and n is 0, then there is atleast one R₁ substituent. In another embodiment, formula IV is subjectto the proviso that when Y is phenyl, R₃ and R₄ are both H, X is CH₂,and n is 0, then if at least one R₁ substituent is —OCH₃, then there isat least one additional R₁ substituent which is not —OCH₃. In anotherembodiment, formula IV is subject to the proviso that when Y is phenyl,R₃ and R₄ are both H, X is CH₂, and n is 0, then if at least one R₁substituent is —OH, then there is at least one additional R₁ substituentwhich is not —OH.

In another embodiment, formula IV is subject to the proviso that when Yis phenyl, R₃ and R₄ are both H, X is O or S, and n is 1, then there isat least one R₁ substituent. In another embodiment, formula IV issubject to the proviso that when Y is phenyl, R₃ and R₄ are both H, X isO or S, and n is 1, then the phenyl substituents are not Cl, —CF₃, or Fin the ortho or para position. In another embodiment, formula IV issubject to the proviso that when Y is phenyl, R₃ and R₄ are both H, X isO or S, and n is 1, then the phenyl substituents are not3-chloro-5-fluoro. In another embodiment, formula IV is subject to theproviso that when Y is phenyl, R₃ and R₄ are both H, X is O or S, and nis 1, then if at least one R₁ substituent is —OCH₃, then there is atleast one additional R₁ substituent is not —OCH₃. In another embodiment,formula IV is subject to the proviso that when Y is phenyl, R₃ and R₄are both H, X is O or S, and n is 1, if at least one R₁ substituent is—OH, then there is at least one additional R₁ substituent which is not—OH.

In another embodiment, formula IV is subject to the proviso that when Yis phenyl, R₃ and R₄ are both H, X is CH₃, and n is 1, then there is atleast one R₁ substituent. In another embodiment, formula IV is subjectto the proviso that when Y is phenyl, R₃ and R₄ are both H, X is CH₃,and n is 1, then the phenyl substituent is not F in the para position.

In another embodiment, formula IV is subject to the proviso that when Yis phenyl, R₃ and R₄ are both H, X is CH₃, and n is 2, then the phenylsubstituents are not 3,4-dimethoxy.

In another embodiment, the present invention relates to any one of thecompounds of general formula IV of the formula:

or any stereoisomer, mixture of stereoisomers, prodrug, metabolite,crystalline form, non-crystalline form, hydrate, solvate, or saltthereof.

In another embodiment, the present invention relates to methods of usingone or more compounds of formula IV-1, IV-2, IV-3, IV-4, IV-5, IV-6,IV-7, IV-8, IV-9, or IV-10 to inhibit SSAO enzyme activity (whether theenzyme activity is due either to soluble SSAO enzyme or membrane-boundVAP 1 protein, or due to both) and/or inhibit binding to VAP-1 protein.The compound(s) can be used for a method of inhibiting SSAO activity orinhibiting binding to VAP-1 in vitro, by supplying the compound(s) tothe in vitro environment in an amount sufficient to inhibit SSAOactivity or inhibit binding to VAP-1. The compound(s) can also be usedfor a method of inhibiting SSAO activity or inhibiting binding to VAP-1in vivo, that is, in a living organism, such as a vertebrate, mammal, orhuman, by administering the compound(s) to the organism in an amountsufficient to inhibit SSAO activity or inhibit binding to VAP-1. Inanother embodiment, the present invention relates to methods of usingone or more compounds of formula IV-1, IV-2, IV-3, IV-4, IV-5, IV-6,IV-7, IV-8, IV-9, or IV-10 to treat or prevent inflammation or immunedisorders. In another embodiment, the present invention relates tomethods of using one or more compounds of formula IV-1, IV-2, IV-3,IV-4, IV-5, IV-6, IV-7, IV-8, IV-9, or IV-10 to suppress or reduceinflammation, or to suppress or reduce an inflammatory response. Inanother embodiment, the present invention relates to methods of treatingor preventing inflammation, by administering one or more compounds offormula IV-1, IV-2, IV-3, IV-4, IV-5, IV-6, IV-7, IV-8, IV-9, or IV-10in a therapeutically effective amount, or in an amount sufficient totreat or prevent inflammation. In another embodiment, the presentinvention relates to methods of treating or preventing immune orautoimmune disorders, by administering one or more compounds of formulaIV-1, IV-2, IV-3, IV-4, IV-5, IV-6, IV-7, IV-8, IV-9, or IV-10 in atherapeutically effective amount, or in an amount sufficient to treat orprevent the immune or autoimmune disorder.

In another embodiment, the present invention relates to a process forpreparing a compound of formula (SI):

-   -   wherein Y is aryl, heteroaryl, or —C₁-C₈ alkyl, optionally        substituted with one, two, three, four, or five groups from R₁,        wherein each R₁ is independently selected from —C₁-C₈ alkyl,        —C₃-C₈ cycloalkyl, —O—C₁-C₈ alkyl, —C₁-C₈ alkyl-O—C₁-C₈ alkyl,        —O—C₃-C₈ cycloalkyl, —O—C₁-C₈ alkyl-C₃-C₈ cycloalkyl, —C₆-C₁₀        aryl, —O—C₁-C₄ alkyl-C₆-C₁₀ aryl, —S—C₁-C₈ alkyl, —S—CF₃, —CF₃,        —OCF₃, —OCH₂CF₃, —CN, —F, —Cl, —Br, —I, —NO₂, —OH, —NHR₄,        —NR₅R₆, and —S(O₂)—(C₁-C₈ alkyl); R₄ is selected from        —C(═O)—(C₁-C₈ alkyl) and —C(═O)—(C₆-C₁₀ aryl); R₅ and R₆ are        independently selected from —H, —C₁-C₈ alkyl, —C₁-C₄        alkyl-C₆-C₁₀ aryl, or R₅ and R₆ together with the nitrogen to        which they are attached form a nitrogen-containing ring; n is        selected from 0, 1, 2, and 3; and PG is a suitable protecting        group; and any stereoisomer, mixture of stereoisomers, prodrug,        metabolite, crystalline form, non-crystalline form, hydrate,        solvate, or salt thereof;        comprising reacting a compound of formula SI-A:    -   wherein PG is defined above; or any stereoisomer, mixture of        stereoisomers, prodrug, metabolite, crystalline form,        non-crystalline form, hydrate, solvate, or salt thereof;        and a compound of formula SI-B:    -   wherein Y and n are as defined above; B is selected from MgX and        Li; and X is selected from —F, —Cl, —Br and —I; or any        stereoisomer, mixture of stereoisomers, prodrug, metabolite,        crystalline form, non-crystalline form, hydrate, solvate, or        salt thereof;        in a suitable solvent (e.g., THF) to form a compound of formula        SI:    -   wherein Y, n, and PG are as defined above; any stereoisomer,        mixture of stereoisomers, prodrug, metabolite, crystalline form,        non-crystalline form, hydrate, solvate, or salt thereof.

In one embodiment of the process for preparing a compound of formula SI,n is 0 or 1. In another embodiment, n is 0. In another embodiment, nis 1. In another embodiment, Y is phenyl, optionally substituted withone or more R₁ substituents. In another embodiment Y is phenyl,optionally substituted with one or more R₁ substituents, and n is 0or 1. In another embodiment, Y is phenyl, optionally substituted withone or more R₁ substituents, and n is 0. In another embodiment, Y isphenyl, optionally substituted with one or more R₁ substituents, and nis 1. In another embodiment, each R₁ is independently selected from—C₁-C₈ alkyl, —C₃-C₈ cycloalkyl, —O—C₁-C₈ alkyl, —O—C₃-C₈ cycloalkyl,—O—C₁-C₈ alkyl-C₃-C₈ cycloalkyl, —C₆-C₁₀ aryl, —O—C₁-C₄ alkyl-C₆-C₁₀aryl, —S—C₁-C₈ alkyl, —CF₃, —OCF₃, —OCH₂CF₃, —CN, —F, —Cl, —Br. Inanother embodiment, Y is phenyl, optionally substituted with one or moreR₁ substituents, n is 0 or 1 and each R₁ is independently selected from—C₁-C₈ alkyl, —C₃-C₈ cycloalkyl, —O—C₁-C₈ alkyl, —O—C₃-C₈ cycloalkyl,—O—C₁-C₈ alkyl-C₃-C₈ cycloalkyl, —C₆-C₁₀ aryl, —O—C₁-C₄ alkyl-C₆-C₁₀aryl, —S—C₁-C₈ alkyl, —CF₃, —OCF₃, —OCH₂CF₃, —CN, —F, —Cl, —Br. Inanother embodiment, Y is phenyl, optionally substituted with one or moreR₁ substituents, n is 0 and each R₁ is independently selected from—C₁-C₈ alkyl, —C₃-C₈ cycloalkyl, —O—C₁-C₈ alkyl, —O—C₃-C₈ cycloalkyl,—O—C₁-C₈ alkyl-C₃-C₈ cycloalkyl, —C₆-C₁₀ aryl, —O—C₁-C₄ alkyl-C₆-C₁₀aryl, S—C₁-C₈ alkyl, —CF₃, —OCF₃, —OCH₂CF₃, —CN, —F, —Cl, —Br. Inanother embodiment, Y is phenyl, optionally substituted with one or moreR₁ substituents, n is 1 and each R₁ is independently selected from—C₁-C₈ alkyl, —C₃-C₈ cycloalkyl, —O—C₁-C₈ alkyl, —O—C₃-C₈ cycloalkyl,—O—C₁-C₈ alkyl-C₃-C₈ cycloalkyl, —C₆-C₁₀ aryl, —O—C₁-C₄ alkyl-C₆-C₁₀aryl, —S—C₁-C₈ alkyl, —CF₃, —OCF₃, —OCH₂CF₃, —CN, —F, —Cl, —Br. Inanother embodiment, Y is phenyl with one R₁ group of the form —OCH₂CH₃.In another embodiment, Y is phenyl with two R₁ groups of the form —OMe.In another embodiment, Y is phenyl, n is 0 and Y has one R₁ group is ofthe form —OCH₂CH₃. In another embodiment, Y is phenyl, n is 0, and Y hastwo R₁ groups of the form —OMe. In another embodiment, Y is phenyl, n is1 and Y has one R₁ group of the form —OCH₂CH₃. In another embodiment, Yis phenyl, n is 1 and Y has two R₁ groups of the form —OMe. In anotherembodiment, the protecting group (PG) is tert-butyloxycarbonyl (BOC). Inanother embodiment, Y is phenyl, optionally substituted with one or moreR₁ substituents, and the protecting group (PG) is tert-butyloxycarbonyl(BOC). In another embodiment, Y is phenyl, optionally substituted withone or more R₁ substituents, n is 0 or 1 and the protecting group (PG)is tert-butyloxycarbonyl (BOC).

In one embodiment of the process for preparing a compound of formula SI,B is magnesium bromide.

In another embodiment, the present invention relates to a process forpreparing a compound of formula SII:

-   -   wherein Y is aryl, heteroaryl, or —C₁-C₈ alkyl, optionally        substituted with one, two, three, four, or five groups from R₁,        wherein each R₁ is independently selected from —H, —C₁-C₈ alkyl,        —C₃-C₈ cycloalkyl, —O—C₁-C₈ alkyl, —C₁-C₈ alkyl-O—C₁-C₈ alkyl,        —O—C₃-C₈ cycloalkyl, —O—C₁-C₈ alkyl-C₃-C₈ cycloalkyl, —C₆-C₁₀        aryl, —O—C₁-C₄ alkyl-C₆-C₁₀ aryl, —S—C₁-C₈ alkyl, —S—CF₃, —CF₃,        —OCF₃, —OCH₂CF₃, —CN, —F, —Cl, —Br, —I, —NO₂, —OH, —NHR₄,        —NR₅R₆, and —S(O₂)—(C₁-C₈ alkyl); R₄ is selected from        —C(═O)—(C₁-C₈ alkyl) and —C(═O)—(C₆-C₁₀ aryl); R₅ and R₆ are        independently selected from —H, —C₁-C₈ alkyl, —C₁-C₄        alkyl-C₆-C₁₀ aryl, or R₅ and R₆ together with the nitrogen to        which they are attached form a nitrogen-containing ring; X is        selected from —CH₂—, —O—, and —S—; n is selected from 0, 1, 2,        and 3; and PG is a suitable protecting group; or any        stereoisomer, mixture of stereoisomers, prodrug, metabolite,        crystalline form, non-crystalline form, hydrate, solvate, or        salt thereof.        comprising the steps of:        (a) reacting a compound of formula SII-A:    -   wherein X, Y, and n are as defined above; or any stereoisomer,        mixture of stereoisomers, prodrug, metabolite, crystalline form,        non-crystalline form, hydrate, solvate, or salt thereof;        with a halogenating agent in a suitable solvent (e.g., DMF or        dichloromethane) to form a compound of formula SII-B:    -   wherein W is selected from —F, —Cl, —Br or —I; and X, Y, and n        are as defined above; or any stereoisomer, mixture of        stereoisomers, prodrug, metabolite, crystalline form,        non-crystalline form, hydrate, solvate, or salt thereof;        (b) reacting the compound of formula SII-B with        (trimethylsilyl)diazomethane (SiMe₃CHN₂) in a suitable solvent        (e.g., dichloromethane) to form a compound of formula SII-C:    -   wherein X, Y, and n are as defined above; or any stereoisomer,        mixture of stereoisomers, prodrug, metabolite, crystalline form,        non-crystalline form, hydrate, solvate, or salt thereof;        (c) reacting the compound of formula SII-C with HZ;    -   wherein Z is selected from —F, —Cl, —Br or —I;        in a suitable solvent (e.g., dichloromethane) to form a compound        of formula SII-D:    -   wherein and X, Y, n, and Z are as defined above; or any        stereoisomer, mixture of stereoisomers, prodrug, metabolite,        crystalline form, non-crystalline form, hydrate, solvate, or        salt thereof;        (d) reacting the compound of formula SII-D with sodium azide        (NaN₃) in a suitable solvent (e.g., DMF) to form a compound of        formula SII-E:    -   wherein X, Y, and n are as defined above; or any stereoisomer,        mixture of stereoisomers, prodrug, metabolite, crystalline form,        non-crystalline form, hydrate, solvate, or salt thereof;        (e) reacting the compound of formula SII-E with an anhydride in        the presence of a reducing agent in a suitable solvent (e.g.,        EtOH) to from a compound of formula SII:    -   wherein X, Y, PG, and n are as defined above; or any        stereoisomer, mixture of stereoisomers, prodrug, metabolite,        crystalline form, non-crystalline form, hydrate, solvate, or        salt thereof.

In one embodiment of the process for preparing a compound of formulaSII, n is 0 or 1. In another embodiment, n is 0. In another embodiment,n is 1. In another embodiment, Y is phenyl, optionally substituted withone or more R₁ substituents. In another embodiment Y is phenyl,optionally substituted with one or more R₁ substituents, and n is 0or 1. In another embodiment, Y is phenyl, optionally substituted withone or more R₁ substituents, and n is 0. In another embodiment, Y isphenyl, optionally substituted with one or more R₁ substituents, and nis 1. In another embodiment X is —CH₂—. In another embodiment X is —O—.In another embodiment X is —S—. In another embodiment X is selected from—CH₂—, —O—, and —S— and n is 1. In another embodiment, each R₁ isindependently selected from —C₁-C₈ alkyl, —C₃-C₈ cycloalkyl, —O—C₁-C₈alkyl, —O—C₃-C₈ cycloalkyl, —O—C₁-C₈ alkyl-C₃-C₈ cycloalkyl, —C₆-C₁₀aryl, —O—C₁-C₄ alkyl-C₆-C₁₀ aryl, —S—C₁-C₈ alkyl, —CF₃, —OCF₃, —OCH₂CF₃,—CN, —F, —Cl, —Br. In another embodiment, Y is phenyl, optionallysubstituted with one or more R₁ substituents, n is 0 or 1 and each R₁ isindependently selected from —C₁-C₈ alkyl, —C₃-C₈ cycloalkyl, —O—C₁-C₈alkyl, —O—C₃-C₈ cycloalkyl, —O—C₁-C₈ alkyl-C₃-C₈ cycloalkyl, —C₆-C₁₀aryl, —O—C₁-C₄ alkyl-C₆-C₁₀ aryl, —S—C₁-C₈ alkyl, —CF₃, —OCF₃, —OCH₂CF₃,—CN, —F, —Cl, —Br. In another embodiment, Y is phenyl, optionallysubstituted with one or more R₁ substituents, n is 0 and each R₁ isindependently selected from —C₁-C₈ alkyl, —C₃-C₈ cycloalkyl, —O—C₁-C₈alkyl, —O—C₃-C₈ cycloalkyl, —O—C₁-C₈ alkyl-C₃-C₈ cycloalkyl, —C₆-C₁₀aryl, —O—C₁-C₄ alkyl-C₆-C₁₀ aryl, —S—C₁-C₈ alkyl, —CF₃, —OCF₃, —OCH₂CF₃,—CN, —F, —Cl, —Br. In another embodiment, Y is phenyl, optionallysubstituted with one or more R₁ substituents, n is 1 and each R₁ isindependently selected from —C₁-C₈ alkyl, —C₃-C₈ cycloalkyl, —O—C₁-C₈alkyl, —O—C₃-C₈ cycloalkyl, —O—C₁-C₈ alkyl-C₃-C₈ cycloalkyl, —C₆-C₁₀aryl, —O—C₁-C₄ alkyl-C₆-C₁₀ aryl, —S—C₁-C₈ alkyl, —CF₃, —OCF₃, —OCH₂CF₃,—CN, —F, —Cl, —Br. In another embodiment, Y is phenyl, optionallysubstituted with one or more R₁ substituents, and one R₁ group is—OCH₂CH₃. In another embodiment, Y is phenyl, optionally substitutedwith one or more R₁ substituents, and two R₁ groups are —OMe. In anotherembodiment, Y is phenyl, optionally substituted with one or more R₁substituents, n is 0 and one R₁ group is —OCH₂CH₃. In anotherembodiment, Y is phenyl, optionally substituted with one or more R₁substituents, n is 0 two R₁ groups are —OMe. In another embodiment, Y isphenyl, optionally substituted with one or more R₁ substituents, n is 1and one R₁ group is —OCH₂CH₃. In another embodiment, Y is phenyl,optionally substituted with one or more R₁ substituents, n is 1 and twoR₁ groups are —OMe. In another embodiment, Z is —Br. In anotherembodiment, the anhydride is tert-butyloxycarbonyl (Boc₂O) and theprotection group (PG) is tert-butyloxycarbonyl (Boc).

In one embodiment of the process for preparing a compound of formulaSII, the halogenating agent is oxalyl chloride (C₂Cl₂O₂) and W is —Cl.In another embodiment, step (a) is carried out in the presence ofdimethylformamide (DMF). In another embodiment, the reducing agent isPd(OH)₂/C. In another embodiment step (e) is carried out in the presenceof Et₃SiH. In another embodiment Z is —Br.

In another embodiment, the present invention relates to a process forpreparing a compound of formula (SIII):

-   -   wherein Y is aryl, heteroaryl, or —C₁-C₈ alkyl, optionally        substituted with one, two, three, four, or five groups from R₁,        wherein each R₁ is independently selected from —C₁-C₈ alkyl,        —C₃-C₈ cycloalkyl, —O—C₁-C₈ alkyl, —C₁-C₈ alkyl-O—C₁-C₈ alkyl,        —O—C₃-C₈ cycloalkyl, —O—C₁-C₈ alkyl-C₃-C₈ cycloalkyl, —C₆-C₁₀        aryl, —O—C₁-C₄ alkyl-C₆-C₁₀ aryl, —S—C₁-C₈ alkyl, —S—CF_(3,),        —CF₃, —OCF₃, —OCH₃CF₃, —CN, —F, —Cl, —Br, —I, —NO₂, —OH, —NHR₄,        —NR₅R₆, and —S(O₂)—(C₁-C₈ alkyl); R₄ is selected from        —C(═O)—(C₁-C₈ alkyl) and —C(═O)—(C₆-C₁₀ aryl); R₅ and R₆ are        independently selected from —H, —C₁-C₈ alkyl, —C₁-C₄        alkyl-C₆-C₁₀ aryl, or R₅ and R₆ together with the nitrogen to        which they are attached form a nitrogen-containing ring; X is        selected from —CH₂—, —O—, and —S—; X₂ is selected from —F, —Cl,        —Br, and —I; n is selected from 0, 1, 2 and 3; and PG is a        suitable protecting group; or any stereoisomer, mixture of        stereoisomers, prodrug, metabolite, crystalline form,        non-crystalline form, hydrate, solvate, or salt thereof;        comprising reacting compound SIII-A:    -   wherein X, Y, n, and PG are as defined above; or any        stereoisomer, mixture of stereoisomers, prodrug, metabolite,        crystalline form, non-crystalline form, hydrate, solvate, or        salt thereof;        with a phosphonium salt in a suitable solvent (e.g., THF) in the        presence of a suitable base to from a mixture of E- and        Z-isomers of formula SIII:    -   wherein X, X₂, Y, n, and PG are as defined above; or any        stereoisomer, mixture of stereoisomers, prodrug, metabolite,        crystalline form, non-crystalline form, hydrate, solvate, or        salt thereof.

In one embodiment of the process for preparing a compound of formulaSIII, n is 0 or 1. In another embodiment, n is 0. In another embodiment,n is 1. In another embodiment, Y is phenyl, optionally substituted withone or more R₁ substituents. In another embodiment Y is phenyl,optionally substituted with one or more R₁ substituents, and n is 0or 1. In another embodiment, Y is phenyl, optionally substituted withone or more R₁ substituents, and n is 0. In another embodiment, Y isphenyl, optionally substituted with one or more R₁ substituents, and nis 1. In another embodiment X is —CH₂—. In another embodiment X is —O—.In another embodiment X is —S—. In another embodiment X is selected from—CH₂—, —O—, and —S— and n is 1. In another embodiment, each R₁ isindependently selected from —C₁-C₈ alkyl, —C₃-C₈ cycloalkyl, —O—C₁-C₈alkyl, —O—C₃-C₈ cycloalkyl, —O—C₁-C₈ alkyl-C₃-C₈ cycloalkyl, —C₆-C₁₀aryl, —O—C₁-C₄ alkyl-C₆-C₁₀ aryl, —S—C₁-C₈ alkyl, —CF₃, —OCF₃, —OCH₂CF₃,—CN, —F, —Cl, —Br. In another embodiment, Y is phenyl, optionallysubstituted with one or more R₁ substituents, n is 0 or 1 and each R₁ isindependently selected from —C₁-C₈ alkyl, —C₃-C₈ cycloalkyl, —O—C₁-C₈alkyl, —O—C₃-C₈ cycloalkyl, —O—C₁-C₈ alkyl-C₃-C₈ cycloalkyl, —C₆-C₁₀aryl, —O—C₁-C₄ alkyl-C₆-C₁₀ aryl, —S—C₁-C₈ alkyl, —CF₃, —OCF₃, —OCH₂CF₃,—CN, —F, —Cl, —Br. In another embodiment, Y is phenyl, optionallysubstituted with one or more R₁ substituents, n is 0 and each R₁ isindependently selected from —C₁-C₈ alkyl, —C₃-C₈ cycloalkyl, —O—C₁-C₈alkyl, —O—C₃-C₈ cycloalkyl, —O—C₁-C₈ alkyl-C₃-C₈ cycloalkyl, —C₆-C₁₀aryl, —O—C₁-C₄ alkyl-C₆-C₁₀ aryl, —S—C₁-C₈ alkyl, —CF₃, —OCF₃, —OCH₂CF₃,—CN, —F, —Cl, —Br. In another embodiment, Y is phenyl, optionallysubstituted with one or more R₁ substituents, n is 1 and each R₁ isindependently selected from —C₁-C₈ alkyl, —C₃-C₈ cycloalkyl, —O—C₁-C₈alkyl, —O—C₃-C₈ cycloalkyl, —O—C₁-C₈ alkyl-C₃-C₈ cycloalkyl, —C₆-C₁₀aryl, —O—C₁-C₄ alkyl-C₆-C₁₀ aryl, —S—C₁-C₈ alkyl, —CF₃, —OCF₃, —OCH₂CF₃,—CN, —F, —Cl, —Br. In another embodiment, Y is phenyl, optionallysubstituted with one or more R₁ substituents, and one R₁ group is—OCH₂CH₃. In another embodiment, Y is phenyl, optionally substitutedwith one or more R₁ substituents, and two R₁ groups are —OMe. In anotherembodiment, Y is phenyl, optionally substituted with one or more R₁substituents, n is 0 and one R₁ group is —OCH₂CH₃. In anotherembodiment, Y is phenyl, optionally substituted with one or more R₁substituents, n is 0, and two R₁ groups are —OMe. In another embodiment,Y is phenyl, optionally substituted with one or more R₁ substituents, nis 1 and one R₁ group is —OCH₂CH₃. In another embodiment, Y is phenyl,optionally substituted with one or more R₁ substituents, n is 1 and twoR₁ groups are —OMe. In another embodiment, X₂ is F or Cl. In anotherembodiment, X₂ is F. In another embodiment, X₂ is Cl. In anotherembodiment, X₂ is F or Cl and n is 0 or 1. In another embodiment, X₂ isF or Cl and n is 0. In another embodiment, X₂ is F or Cl and n is 1. Inanother embodiment, X₂ is F or Cl, n is 0 or 1, and X is —CH₂—. Inanother embodiment, X₂ is F or Cl, n is 1, and X is —O—. In anotherembodiment, the protection group (PG) is tert-butyloxycarbonyl (Boc).

In one embodiment of the process for preparing a compound of formulaSIII, the process for preparing a compound of formula SIII furthercomprises separation of the isomeric mixture. In another embodiment, theprocess comprises separation of the isomeric mixture by columnchromatography. In another embodiment, the process further comprises theprocess for preparing SI for use as SIII-A. In another embodiment, theprocess further comprises the process for preparing SII for use asSIII-A. In another embodiment, the phosphonium salt isfluoromethyltriphenylphosphonium tetrafluoroborate (FCH₂PPh₃ ⁺BF₄ ⁻) andthe base is sodium hydride (NaH).

In one embodiment of the process for preparing a compound of formulaSIII, the Z enantiomer of SIII is produced in an amount greater thanabout 50%, greater than about 60%, greater than about 70%, greater thanabout 80%, greater than about 85%, greater than about 90%, greater thanabout 95%, greater than about 97%, greater than about 98%, or greaterthan about 99%.

In another embodiment, the process for preparing a compound of formulaSIII further comprises removing the protecting group (PG) from SIII in asuitable solvent (e.g., dichloromethane) to form a compound of formulaSIV:

-   -   wherein X, Y, X₂, and n are as defined above; or any        stereoisomer, mixture of stereoisomers, prodrug, metabolite,        crystalline form, non-crystalline form, hydrate, solvate, or        salt thereof.

In one embodiment of the process for preparing a compound of formulaSIV, the protecting group (PG) is removed with a strong acid. In anotherembodiment, the protecting group (PG) is removed with trifluoroaceticacid (TFA).

In another embodiment, the present invention relates to a process forpreparing a compound of formula SV:

-   -   wherein Y is aryl, heteroaryl, or —C₁-C₈ alkyl, optionally        substituted with one, two, three, four, or five groups from R₁,        wherein each R₁ is independently selected from —C₁-C₈ alkyl,        —C₃-C₈ cycloalkyl, —O—C₁-C₈ alkyl, —C₁-C₈ alkyl-O—C₁-C₈ alkyl,        —O—C₃-C₈ cycloalkyl, —O—C₁-C₈ alkyl-C₃-C₈ cycloalkyl, —C₆-C₁₀        aryl, —O—C₁-C₄ alkyl-C₆-C₁₀ aryl, —S—C₁-C₈ alkyl, —S—CF₃, —CF₃,        —OCF₃, —OCH₃CF₃, —CN, —F, —Cl, —Br, —I, —NO₂, —OH, —NHR₄,        —NR₅R₆, and —S(O₂)—(C₁-C₈ alkyl); R₄ is selected from        —C(═O)—(C₁-C₈ alkyl) and —C(═O)—(C₆-C₁₀ aryl); R₅ and R₆ are        independently selected from —H, —C₁-C₈ alkyl, —C₁-C₄        alkyl-C₆-C₁₀ aryl, or R₅ and R₆ together with the nitrogen to        which they are attached form a nitrogen-containing ring; X is        selected from —CH₂—, —O—, and —S—; n is selected from 0, 1, 2        and 3; and R₇ is selected from —H, —F, —C₁-C₄ alkyl, and —CF₃;        or any stereoisomer, mixture of stereoisomers, prodrug,        metabolite, crystalline form, non-crystalline form, hydrate,        solvate, or salt thereof;        comprising the steps of:        (a) reacting a compound of formula SV-A:    -   wherein X, Y, and n are as defined above; or any stereoisomer,        mixture of stereoisomers, prodrug, metabolite, crystalline form,        non-crystalline form, hydrate, solvate, or salt thereof;        with R₈OH and an acid;    -   wherein R₈ is selected from —C₁-C₈ alkyl, —C₃-C₈ cycloalkyl, or        —C₆-C₁₀ aryl; or any stereoisomer, mixture of stereoisomers,        prodrug, metabolite, crystalline form, non-crystalline form,        hydrate, solvate, or salt thereof;        in a suitable solvent (e.g., MeOH) to form a compound of formula        SV-B:    -   wherein X, Y, R₈, and n are as defined above; or any        stereoisomer, mixture of stereoisomers, prodrug, metabolite,        crystalline form, non-crystalline form, hydrate, solvate, or        salt thereof;        (b) reacting the compound of formula SV-B with a reducing agent        in a suitable solvent (e.g., dichloromethane) to form a compound        of formula SV-C:    -   wherein X, Y, and n are as defined above; or any stereoisomer,        mixture of stereoisomers, prodrug, metabolite, crystalline form,        non-crystalline form, hydrate, solvate, or salt thereof;        (c) reacting the compound of formula SV-C with a phosphonate        ester in a suitable solvent (e.g., THF) in the presence of a        suitable base to from a mixture of E- and Z-isomers of formula        SV-D:    -   wherein X, Y, R₇ and n are as defined above; and    -   R₉ is selected from —C₁-C₈ alkyl, —C₃-C₈ cycloalkyl, and —C₆-C₁₀        aryl; or any stereoisomer, mixture of stereoisomers, prodrug,        metabolite, crystalline form, non-crystalline form, hydrate,        solvate, or salt thereof;        (d) reacting the compound of formula SV-D with a reducing agent        in a suitable solvent (e.g., hexane or toluene) to form a        compound of formula SV-E:    -   wherein X, Y, R₇ and n are defined above; or any stereoisomer,        mixture of stereoisomers, prodrug, metabolite, crystalline form,        non-crystalline form, hydrate, solvate, or salt thereof;        (e) reacting the compound of formula SV-E with phthalimide in        the presence of a phosphine and an azodicarboxylate reagent in a        suitable solvent (e.g., THF) to form a compound of formula SV:

wherein X, Y, R₇ and n are defined above; or any stereoisomer, mixtureof stereoisomers, prodrug, metabolite, crystalline form, non-crystallineform, hydrate, solvate, or salt thereof.

In one embodiment of the process for preparing a compound of formula SV,n is 0 or 1. In another embodiment, n is 0. In another embodiment, nis 1. In another embodiment, Y is phenyl, optionally substituted withone or more R₁ substituents. In another embodiment Y is phenyl,optionally substituted with one or more R₁ substituents, and n is 0or 1. In another embodiment, Y is phenyl, optionally substituted withone or more R₁ substituents, and n is 0. In another embodiment, Y isphenyl, optionally substituted with one or more R₁ substituents, and nis 1. In another embodiment X is —CH₂—. In another embodiment X is —O—.In another embodiment X is —S—. In another embodiment X is selected from—CH₂—, —O—, and —S— and n is 1. In another embodiment, each R₁ isindependently selected from —C₁-C₈ alkyl, —O—C₁-C₈ alkyl, —C₁-C₈alkyl-O—C₁-C₈ alkyl, —S—C₁-C₈ alkyl, —CF₃, —OCF₃, —F, —S(O₂)—(C₁-C₈alkyl), and —NR₅R₆. In another embodiment, Y is phenyl, optionallysubstituted with one or more R₁ substituents, n is 0 or 1 and each R₁ isindependently selected from —C₁-C₈ alkyl, —O—C₁-C₈ alkyl, —C₁-C₈alkyl-O—C₁-C₈ alkyl, —S—C₁-C₈ alkyl, —CF₃, —OCF₃, —F, —S(O₂)—(C₁-C₈alkyl), and —NR₅R₆. In another embodiment, Y is phenyl, optionallysubstituted with one or more R₁ substituents, n is 0 and each R₁ isindependently selected from —C₁-C₈ alkyl, —O—C₁-C₈ alkyl, —C₁-C₈alkyl-O—C₁-C₈ alkyl, —S—C₁-C₈ alkyl, —CF₃, —OCF₃, —F, —S(O₂)—(C₁-C₈alkyl), and —NR₅R₆. In another embodiment, Y is phenyl, optionallysubstituted with one or more R₁ substituents, n is 1 and each R₁ isindependently selected from —C₁-C₈ alkyl, —O—C₁-C₈ alkyl, —C₁-C₈alkyl-O—C₁-C₈ alkyl, —S—C₁-C₈ alkyl, —CF₃, —OCF₃, —F, —S(O₂)—(C₁-C₈alkyl), and —NR₅R₆. In another embodiment, R₇ is —F. In anotherembodiment, Y is phenyl, optionally substituted with one or more R₁substituents, and R₇ is —F. In another embodiment, Y is phenyl,optionally substituted with one or more R₁ substituents, n is 0 and R₇is —F. In another embodiment, Y is phenyl, optionally substituted withone or more R₁ substituents, n is 0, X is —CH₃—, and R₇ is —F.

In one embodiment, the process for preparing a compound of formula SVfurther comprises separation of the isomeric mixture. In anotherembodiment, the process further comprises separation of the isomericmixture by column chromatography. In another embodiment, R₈ is -Me. Inanother embodiment, the acid is H₂SO₄. In another embodiment, thereducing agent in step (b) is diisobutylaluminum hydride (DIBAL-H). Inanother embodiment, the reducing agent in step (d) is diisobutylaluminumhydride (DIBAL-H). In another embodiment, for step (c) the phosphonateester is triethyl-2-fluoro-2-phosphoacetate, R₉ is —CH₂CH₃, and the baseis isopropylmagnesium chloride (i-PrMgCl). In another embodiment, thephosphine is triphenyl phosphine (PPh₃) and the azodicarboxylate isdiisopropyl azodicarboxylate (DIAD).

In one embodiment of the process for preparing a compound of formula SV,the Z enantiomer of SV is produced in an amount greater than about 50%,greater than about 60%, greater than about 70%, greater than about 80%,greater than about 85%, greater than about 90%, greater than about 95%,greater than about 97%, greater than about 98%, or greater than about99%. In another embodiment, the E enantiomer of SV is produced in anamount greater than about 50%, greater than about 60%, greater thanabout 70%, greater than about 80%, greater than about 85%, greater thanabout 90%, greater than about 95%, greater than about 97%, greater thanabout 98%, or greater than about 99%.

In another embodiment, the process for preparing a compound of formulaSV further comprises removing the N-phthalimido protecting group (PG)from SV in a suitable solvent (e.g., ethanol, followed by diethyl etherwhen forming and isolating the salt form) to form a compound of formulaSVI:

-   -   wherein Y, X, R₇, and n are defined above; or any stereoisomer,        mixture of stereoisomers, prodrug, metabolite, crystalline form,        non-crystalline form, hydrate, solvate, or salt thereof.

In one embodiment of the process for preparing a compound of formulaSVI, the N-phthalimido protecting group (PG) is removed using hydrazine.In another embodiment, the N-phthalimido protecting group (PG) isremoved using a primary amine. In another embodiment, the N-phthalimidoprotecting group (PG) is removed using a methyl amine.

In another embodiment, the present invention relates to a process forpreparing a compound of formula SVII:

-   -   wherein Y is aryl, heteroaryl, or —C₁-C₈ alkyl, optionally        substituted with one, two, three, four, or five groups from R₁,        wherein each R₁ is independently selected from —C₁-C₈ alkyl,        —C₃-C₈ cycloalkyl, —O—C₁-C₈ alkyl, —C₁-C₈ alkyl-O—C₁-C₈ alkyl,        —O—C₃-C₈ cycloalkyl, —O—C₁-C₈ alkyl-C₃-C₈ cycloalkyl, —C₆-C₁₀        aryl, —O—C₁-C₄ alkyl-C₆-C₁₀ aryl, —S—C₁-C₈ alkyl, —S—CF₃, —CF₃,        —OCF₃, —OCH₃CF₃, —CN, —F, —Cl, —Br, —I, —NO₂, —OH, —NHR₄,        —NR₅R₆, and —S(O₂)—(C₁-C₈ alkyl); R₄ is selected from        —C(═O)—(C₁-C₈ alkyl) and —C(═O)—(C₆-C₁₀ aryl); R₅ and R₆ are        independently selected from —H, —C₁-C₈ alkyl, —C₁-C₄        alkyl-C₆-C₁₀ aryl, or R₅ and R₆ together with the nitrogen to        which they are attached form a nitrogen-containing ring; X is        selected from —O— and —S—; n is selected from 1, 2 and 3; and R₇        is selected from —H, —F, —C₁-C₄ alkyl, and —CF₃; and PG is a        suitable protecting group; or any stereoisomer, mixture of        stereoisomers, prodrug, metabolite, crystalline form,        non-crystalline form, hydrate, solvate, or salt thereof;        comprising:        reacting a compound of formula SVII-A:    -   wherein R₇, n, and PG are as defined above; or any stereoisomer,        mixture of stereoisomers, prodrug, metabolite, crystalline form,        non-crystalline form, hydrate, solvate, or salt thereof;        and a compound of formula SVII-B:        Y—X—H   (SVII-B)    -   wherein Y and X are defined above; or any stereoisomer, mixture        of stereoisomers, prodrug, metabolite, crystalline form,        non-crystalline form, hydrate, solvate, or salt thereof;        in the presence of a phosphine and an azodicarboxylate reagent        in a suitable solvent (e.g., THF) to form a compound of formula        SVII:    -   wherein A, Y, R₇, n, and PG are defined above; or any        stereoisomer, mixture of stereoisomers, prodrug, metabolite,        crystalline form, non-crystalline form, hydrate, solvate, or        salt thereof.

In one embodiment of the process for preparing a compound of formulaSVII, n is 1. In another embodiment, Y is phenyl, optionally substitutedwith one or more R₁ substituents. In another embodiment Y is phenyl,optionally substituted with one or more R₁ substituents, and n is 1. Inanother embodiment X is —O—. In another embodiment X is —S—. In anotherembodiment X is —O— and n is 1. In another embodiment X is —S— and nis 1. In another embodiment X is —O—, n is 1, and Y is phenyl,optionally substituted with one or more R₁ substituents. In anotherembodiment X is —S—, n is 1, and Y is phenyl, optionally substitutedwith one or more R₁ substituents. In another embodiment, each R₁ isindependently selected from —C₁-C₈ alkyl, —O—C₁-C₈ alkyl, —C₁-C₈alkyl-O—C₁-C₈ alkyl, —S—C₁-C₈ alkyl, —CF₃, —OCF₃, —F, —S(O₂)—(C₁-C₈alkyl), and —NR₅R₆. In another embodiment, Y is phenyl, optionallysubstituted with one or more R₁ substituents, n is 0 or 1 and each R₁ isindependently selected from —C₁-C₈ alkyl, —O—C₁-C₈ alkyl, —C₁-C₈alkyl-O—C₁-C₈ alkyl, —S—C₁-C₈ alkyl, —CF₃, —OCF₃, —F, —S(O₂)—(C₁-C₈alkyl), and —NR₅R₆. In another embodiment, Y is phenyl, optionallysubstituted with one or more R₁ substituents, n is 0 and each R₁ isindependently selected from —C₁-C₈ alkyl, —O—C₁-C₈ alkyl, —C₁-C₈alkyl-O—C₁-C₈ alkyl, —S—C₁-C₈ alkyl, —CF₃, —OCF₃, —F, —S(O₂)—(C₁-C₈alkyl), and —NR₅R₆. In another embodiment, Y is phenyl, optionallysubstituted with one or more R₁ substituents, n is 1 and each R₁ isindependently selected from —C₁-C₈ alkyl, —O—C₁-C₈ alkyl, —C₁-C₈alkyl-O—C₁-C₈ alkyl, —S—C₁-C₈ alkyl, —CF₃, —OCF₃, —F, —S(O₂)—(C₁-C₈alkyl), and —NR₅R₆. In another embodiment, R₇ is —F. In anotherembodiment, Y is phenyl, optionally substituted with one or more R₁substituents, and R₇ is —F. In another embodiment, Y is phenyl,optionally substituted with one or more R₁ substituents, n is 1 and R₇is —F. In another embodiment, the protection group (PG) istert-butyloxycarbonyl (Boc).

In one embodiment, the process for preparing a compound of formula SVIIfurther comprises separation of the isomeric mixture. In anotherembodiment, the process comprises separation of the isomeric mixture bycolumn chromatography. In another embodiment, the phosphine is triphenylphosphine (PPh₃) and the azodicarboxylate is diisopropylazodicarboxylate (DIAD).

In one embodiment of the process for preparing a compound of formulaSVII, the Z enantiomer of SVII is produced in an amount greater thanabout 50%, greater than about 60%, greater than about 70%, greater thanabout 80%, greater than about 85%, greater than about 90%, greater thanabout 95%, greater than about 97%, greater than about 98%, or greaterthan about 99%. In another embodiment, the E enantiomer of SVII isproduced in an amount greater than about 50%, greater than about 60%,greater than about 70%, greater than about 80%, greater than about 85%,greater than about 90%, greater than about 95%, greater than about 97%,greater than about 98%, or greater than about 99%.

In another embodiment, the process for preparing a compound of formulaSVII further comprises removing the protecting group (PG) from SVII in asuitable solvent (e.g., dichloromethane, followed by diethyl ether whenforming and isolating the salt) to form a compound of formula SVIII:

-   -   wherein X, Y, n, and R₇ are as defined above; or any        stereoisomer, mixture of stereoisomers, prodrug, metabolite,        crystalline form, non-crystalline form, hydrate, solvate, or        salt thereof.

In one embodiment of the process for preparing a compound of formulaSVIII, the protecting group (PG) is removed with a strong acid. Inanother embodiment, the protecting group (PG) is removed withtrifluoroacetic acid (TFA).

In another embodiment, the present invention relates to a process forpreparing a compound of formula SIX:

-   -   wherein Y is aryl, heteroaryl, or —C₁-C₈ alkyl, optionally        substituted with one, two, three, four, or five groups from R₁,        wherein each R₁ is independently selected from —C₁-C₈ alkyl,        —C₃-C₈ cycloalkyl, —O—C₁-C₈ alkyl, —C₁-C₈ alkyl-O—C₁-C₈ alkyl,        —O—C₃-C₈ cycloalkyl, —O—C₁-C₈ alkyl-C₃-C₈ cycloalkyl, —C₆-C₁₀        aryl, —O—C₁-C₄ alkyl-C₆-C₁₀ aryl, —S—C₁-C₈ alkyl, —S—CF₃, —CF₃,        —OCF₃, —OCH₃CF₃, —CN, —F, —Cl, —Br, —I, —NO₂, —OH, —NHR₄,        —NR₅R₆, and —S(O₂)—(C₁-C₈ alkyl); R₄ is selected from        —C(═O)—(C₁-C₈ alkyl) and —C(═O)—(C₆-C₁₀ aryl); R₅ and R₆ are        independently selected from —H, —C₁-C₈ alkyl, —C₁-C₄        alkyl-C₆-C₁₀ aryl, or R₅ and R₆ together with the nitrogen to        which they are attached form a nitrogen-containing ring; n is        selected from 1, 2 and 3; and R₇ is selected from —H, —F, —C₁-C₄        alkyl, and —CF₃; and PG is a suitable protecting group; or any        stereoisomer, mixture of stereoisomers, prodrug, metabolite,        crystalline form, non-crystalline form, hydrate, solvate, or        salt thereof; comprising:        reacting a compound of formula SIX-A:    -   wherein X is selected from —F, —Cl, —Br, and —I;    -   and R₇, PG, and n are as defined above; or any stereoisomer,        mixture of stereoisomers, prodrug, metabolite, crystalline form,        non-crystalline form, hydrate, solvate, or salt thereof;        and a compound of formula SIX-B:        Y—B(OH)₂   (SIX-B)    -   wherein Y is defined above; or any stereoisomer, mixture of        stereoisomers, prodrug, metabolite, crystalline form,        non-crystalline form, hydrate, solvate, or salt thereof;        in the presence of a metal complex in a suitable solvent (e.g.,        benzene) to form a compound of formula SIX:    -   wherein Y, R₇, n, and PG are defined above; or any stereoisomer,        mixture of stereoisomers, prodrug, metabolite, crystalline form,        non-crystalline form, hydrate, solvate, or salt thereof.

In one embodiment of the process for preparing a compound of formulaSIX, n is 1. In another embodiment, Y is phenyl, optionally substitutedwith one or more R₁ substituents. In another embodiment Y is phenyl,optionally substituted with one or more R₁ substituents, and n is 1. Inanother embodiment, each R₁ is independently selected from —C₁-C₈ alkyl,—O—C₁-C₈ alkyl, —C₁-C₈ alkyl-O—C₁-C₈ alkyl, —S—C₁-C₈ alkyl, —CF₃, —OCF₃,—F, —S(O₂)—(C₁-C₈ alkyl), and —NR₅R₆. In another embodiment, Y isphenyl, optionally substituted with one or more R₁ substituents, n is Iand each R₁ is independently selected from —C₁-C₈ alkyl, —O—C₁-C₈ alkyl,—C₁-C₈ alkyl-O—C₁-C₈ alkyl, —S—C₁-C₈ alkyl, —CF₃, —OCF₃, —F,—S(O₂)—(C₁-C₈ alkyl), and —NR₅R₆. In another embodiment, R₇ is —F. Inanother embodiment, Y is phenyl, optionally substituted with one or moreR₁ substituents, and R₇ is —F. In another embodiment, Y is phenyl,optionally substituted with one or more R₁ substituents, n is 1 and R₇is —F.

In another embodiment, the process for preparing a compound of formulaSIX further comprises separation of the isomeric mixture. In anotherembodiment, the process further comprises separation of the isomericmixture by column chromatography. In another embodiment, the metalcomplex contains palladium. In another embodiment, the metal complex isBis(dibenzylideneacetone)Pd(0).

In one embodiment of the process for preparing a compound of formulaSIX, the Z enantiomer of SIX is produced in an amount greater than about50%, greater than about 60%, greater than about 70%, greater than about80%, greater than about 85%, greater than about 90%, greater than about95%, greater than about 97%, greater than about 98%, or greater thanabout 99%. In another embodiment, the E enantiomer of SV is produced inan amount greater than about 50%, greater than about 60%, greater thanabout 70%, greater than about 80%, greater than about 85%, greater thanabout 90%, greater than about 95%, greater than about 97%, greater thanabout 98%, or greater than about 99%.

In another embodiment, the process for preparing a compound of formulaSIX further comprises removing the protecting group (PG) from SIX in asuitable solvent (e.g., dichloromethane, followed by diethyl ether whenforming and isolating the salt) to form a compound of formula SX:

-   -   wherein Y, n, and R₇ are as defined above; or any stereoisomer,        mixture of stereoisomers, prodrug, metabolite, crystalline form,        non-crystalline form, hydrate, solvate, or salt thereof.

In one embodiment of the process for preparing a compound of formulaSVIII, the protecting group (PG) is removed with a strong acid. Inanother embodiment, the protecting group (PG) is removed withtrifluoroacetic acid (TFA).

In another embodiment, the present invention relates to methods of usingone or more compounds of formula I, I-P, I-E, I-P-E, I-P-Z, I-A, I-AP,I-A-E, I-AP-E, I-A-Z, I-AP-Z, I-B, I-BP, I-B-E, I-BP-E, I-B-Z, I-BP-Z,any one of I-1 through I-109, II, II-E, II-Z, II-A, II-A-E, II-A-Z,II-B, II-B-E, II-B-Z, any one of II-1 through II-23, IV, and any one ofIV-1 through IV-10 to inhibit SSAO enzyme activity (whether the enzymeactivity is due either to soluble SSAO enzyme or membrane-bound VAP-1protein, or due to both) and/or inhibit binding to VAP-1 protein. Thecompound(s) can be used for a method of inhibiting SSAO activity orinhibiting binding to VAP-1 in vitro, by supplying the compound to thein vitro environment in an amount sufficient to inhibit SSAO activity orinhibit binding to VAP-1. The compound(s) can also be used for a methodof inhibiting SSAO activity or inhibiting binding to VAP-1 in vivo, thatis, in a living organism, such as a vertebrate, mammal, or human, byadministering the compound to the organism in an amount sufficient toinhibit SSAO activity or inhibit binding to VAP-1. In other embodimentsof the invention, one or more compounds of formula I, I-P, I-E, I-P-E,I-P-Z, I-A, I-AP, I-A-E, I-AP-E, I-A-Z, I-AP-Z, I-B, I-BP, I-B-E,I-BP-E, I-B-Z, I-BP-Z, any one of I-1 through I-109, II, II-E, II-Z,II-A, II-A-E, II-A-Z, II-B, II-B-E, II-B-Z, any one of II-1 throughII-23, IV, and any one of IV-1 through IV-10 is administered to asubject or patient in an amount sufficient to inhibit SSAO enzymeactivity (whether the enzyme activity is due either to soluble SSAOenzyme or membrane-bound VAP-1 protein, or due to both) and/or inhibitbinding to VAP-1 protein by at least about 50% or more than about 50%,while inhibiting MAO, MAO-A, MAO-B, or both MAO-A and MAO-B activity byno more than about 25%. In other embodiments of the invention, one ormore compounds of formula I, I-P, I-E, I-P-E, I-P-Z, I-A, I-AP, I-A-E,I-AP-E, I-A-Z, I-AP-Z, I-B, I-BP, I-B-E, I-BP-E, I-B-Z, I-BP-Z, any oneof I-1 through I-109, II, II-E, II-Z, II-A, II-A-E, II-A-Z, II-B,II-B-E, II-B-Z, any one of II-1 through II-23, IV, and any one of IV-1through IV-10 is administered to a subject or patient in an amountsufficient to inhibit SSAO enzyme activity (whether the enzyme activityis due either to soluble SSAO enzyme or membrane-bound VAP-1 protein, ordue to both) and/or inhibit binding to VAP-1 protein by at least about75% or more than about 75%, while inhibiting MAO, MAO-A, MAO-B, or bothMAO-A and MAO-B activity by no more than about 25%. In other embodimentsof the invention, one or more compounds of formula I, I-P, I-E, I-P-E,I-P-Z, I-A, I-AP, I-A-E, I-AP-E, I-A-Z, I-AP-Z, I-B, I-BP, I-B-E,I-BP-E, I-B-Z, I-BP-Z, any one of I-1 through I-109, II, II-E, II-Z,II-A, II-A-E, II-A-Z, II-B, II-B-E, II-B-Z, any one of II-1 throughII-23, IV, and any one of IV-1 through IV-10 is administered to asubject or patient in an amount sufficient to inhibit SSAO enzymeactivity (whether the enzyme activity is due either to soluble SSAOenzyme or membrane-bound VAP-1 protein, or due to both) and/or inhibitbinding to VAP-1 protein by at least about 75% or more than about 75%,while inhibiting MAO, MAO-A, MAO-B, or both MAO-A and MAO-B activity byno more than about 10%. In other embodiments of the invention, one ormore compounds of formula I, I-P, I-E, I-P-E, I-P-Z, I-A, I-AP, I-A-E,I-AP-E, I-A-Z, I-AP-Z, I-B, I-BP, I-B-E, I-BP-E, I-B-Z, I-BP-Z, any oneof I-1 through I-109, II, II-E, II-Z, II-A, II-A-E, II-A-Z, II-B,II-B-E, II-B-Z, any one of II-1 through II-23, IV, and any one of IV-1through IV-10 is administered to a subject or patient in an amountsufficient to inhibit SSAO enzyme activity (whether the enzyme activityis due either to soluble SSAO enzyme or membrane-bound VAP-1 protein, ordue to both) and/or inhibit binding to VAP-1 protein by at least about90% or more than about 90%, while inhibiting MAO, MAO-A, MAO-B, or bothMAO-A and MAO-B activity by no more than about 10%.

In other embodiments, the invention embraces unit dosage formulations ofone or more compounds of formula I, I-P, I-E, I-P-E, I-P-Z, I-A, I-AP,I-A-E, I-AP-E, I-A-Z, I-AP-Z, I-B, I-BP, I-B-E, I-BP-E, I-B-Z, I-BP-Z,any one of I-1 through I-109, II, II-E, II-Z, II-A, II-A-E, II-A-Z,II-B, II-B-E, II-B-Z, any one of II-1 through II-23, IV, and any one ofIV-1 through IV-10 which, when administered to a subject, is sufficientto inhibit SSAO enzyme activity (whether the enzyme activity is dueeither to soluble SSAO enzyme or membrane-bound VAP-1 protein, or due toboth) and/or inhibit binding to VAP-1 protein by at least about 50% ormore than about 50%, while inhibiting MAO, MAO-A, MAO-B, or both MAO-Aand MAO-B activity by no more than about 25%; or is sufficient toinhibit SSAO enzyme activity (whether the enzyme activity is due eitherto soluble SSAO enzyme or membrane-bound VAP-1 protein, or due to both)and/or inhibit binding to VAP-1 protein by at least about 75% or morethan about 75%, while inhibiting MAO, MAO-A, MAO-B, or both MAO-A andMAO-B activity by no more than about 25%; or is sufficient to inhibitSSAO enzyme activity (whether the enzyme activity is due either tosoluble SSAO enzyme or membrane-bound VAP-1 protein, or due to both)and/or inhibit binding to VAP-1 protein by at least about 75% or morethan about 75%, while inhibiting MAO, MAO-A, MAO-B, or both MAO-A andMAO-B activity by no more than about 10%; or is sufficient to inhibitSSAO enzyme activity (whether the enzyme activity is due either tosoluble SSAO enzyme or membrane-bound VAP-1 protein, or due to both)and/or inhibit binding to VAP-1 protein by at least about 90% or morethan about 90%, while inhibiting MAO, MAO-A, MAO-B, or both MAO-A andMAO-B activity by no more than about 10%.

In other embodiments of the invention, one or more compounds of formulaI, I-P, I-E, I-P-E, I-P-Z, I-A, I-AP, I-A-E, I-AP-E, I-A-Z, I-AP-Z, I-B,I-BP, I-B-E, I-BP-E, I-B-Z, I-BP-Z, any one of I-1 through I-109, II,II-E, II-Z, II-A, II-A-E, II-A-Z, II-B, II-B-E, II-B-Z, any one of II-1through II-23, IV, and any one of IV-1 through IV-10 is administered toa subject or patient in an amount sufficient to inhibit SSAO enzymeactivity (whether the enzyme activity is due either to soluble SSAOenzyme or membrane-bound VAP-1 protein, or due to both) and/or inhibitbinding to VAP-1 protein by at least about 50% or more than about 50%,while inhibiting diamine oxidase activity by no more than about 25%. Inother embodiments of the invention, one or more compounds of formula I,I-P, I-E, I-P-E, I-P-Z, I-A, I-AP, I-A-E, I-AP-E, I-A-Z, I-AP-Z, I-B,I-BP, I-B-E, I-BP-E, I-B-Z, I-BP-Z, any one of I-1 through I-109, II,II-E, II-Z, II-A, II-A-E, II-A-Z, II-B, II-B-E, II-B-Z, any one of II-1through II-23, IV, and any one of IV-1 through IV-10 is administered toa subject or patient in an amount sufficient to inhibit SSAO enzymeactivity (whether the enzyme activity is due either to soluble SSAOenzyme or membrane-bound VAP-1 protein, or due to both) and/or inhibitbinding to VAP-1 protein by at least about 75% or more than about 75%,while inhibiting diamine oxidase activity by no more than about 25%. Inother embodiments of the invention, one or more compounds of formula I,I-P, I-E, I-P-E, I-P-Z, I-A, I-AP, I-A-E, I-AP-E, I-A-Z, I-AP-Z, I-B,I-BP, I-B-E, I-BP-E, I-B-Z, I-BP-Z, any one of I-1 through I-109, II,II-E, II-Z, II-A, II-A-E, II-A-Z, II-B, II-B-E, II-B-Z, any one of II-1through II-23, IV, and any one of IV-1 through IV-10 is administered toa subject or patient in an amount sufficient to inhibit SSAO enzymeactivity (whether the enzyme activity is due either to soluble SSAOenzyme or membrane-bound VAP-1 protein, or due to both) and/or inhibitbinding to VAP-1 protein by at least about 75% or more than about 75%,while inhibiting diamine oxidase activity by no more than about 10%. Inother embodiments of the invention, one or more compounds of formula I,I-P, I-E, I-P-E, I-P-Z, I-A, I-AP, I-A-E, I-AP-E, I-A-Z, I-AP-Z, I-B,I-BP, I-B-E, I-BP-E, I-B-Z, I-BP-Z, any one of I-1 through I-109, II,II-E, II-Z, II-A, II-A-E, II-A-Z, II-B, II-B-E, II-B-Z, any one of II-1through II-23, IV, and any one of IV-1 through IV-10 is administered toa subject or patient in an amount sufficient to inhibit SSAO enzymeactivity (whether the enzyme activity is due either to soluble SSAOenzyme or membrane-bound VAP-1 protein, or due to both) and/or inhibitbinding to VAP-1 protein by at least about 90% or more than about 90%,while inhibiting diamine oxidase activity by no more than about 10%.

In other embodiments, the invention embraces unit dosage formulations ofone or more compounds of formula I, I-P, I-E, I-P-E, I-P-Z, I-A, I-AP,I-A-E, I-AP-E, I-A-Z, I-AP-Z, I-B, I-BP, I-B-E, I-BP-E, I-B-Z, I-BP-Z,any one of I-1 through I-109, II, II-E, II-Z, II-A, II-A-E, II-A-Z,II-B, II-B-E, II-B-Z, any one of II-1 through II-23, IV, and any one ofIV-1 through IV-10 which, when administered to a subject, is sufficientto inhibit SSAO enzyme activity (whether the enzyme activity is dueeither to soluble SSAO enzyme or membrane-bound VAP-1 protein, or due toboth) and/or inhibit binding to VAP-1 protein by at least about 50% ormore than about 50%, while inhibiting diamine oxidase activity by nomore than about 25%; or is sufficient to inhibit SSAO enzyme activity(whether the enzyme activity is due either to soluble SSAO enzyme ormembrane-bound VAP-1 protein, or due to both) and/or inhibit binding toVAP-1 protein by at least about 75% or more than about 75%, whileinhibiting diamine oxidase activity by no more than about 25%; or issufficient to inhibit SSAO enzyme activity (whether the enzyme activityis due either to soluble SSAO enzyme or membrane-bound VAP-1 protein, ordue to both) and/or inhibit binding to VAP-1 protein by at least about75% or more than about 75%, while inhibiting diamine oxidase activity byno more than about 10%; or is sufficient to inhibit SSAO enzyme activity(whether the enzyme activity is due either to soluble SSAO enzyme ormembrane-bound VAP-1 protein, or due to both) and/or inhibit binding toVAP-1 protein by at least about 90% or more than about 90%, whileinhibiting diamine oxidase activity by no more than about 10%.

In other embodiments of the invention, one or more compounds of formulaI, I-P, I-E, I-P-E, I-P-Z, I-A, I-AP, I-A-E, I-AP-E, I-A-Z, I-AP-Z, I-B,I-BP, I-B-E, I-BP-E, I-B-Z, I-BP-Z, any one of I-1 through I-109, II,II-E, II-Z, II-A, II-A-E, II-A-Z, II-B, II-B-E, II-B-Z, any one of II-1through II-23, IV, and any one of IV-1 through IV-10, but excludingcompound I-1-Z, is administered to a subject or patient in an amountsufficient to inhibit SSAO enzyme activity (whether the enzyme activityis due either to soluble SSAO enzyme or membrane-bound VAP-1 protein, ordue to both) and/or inhibit binding to VAP-1 protein by at least about50% or more than about 50%, while binding to a receptor or transporter(where the compound may inhibit, antagonize, activate, or agonize thereceptor or transporter) listed in Table 2-A, Table 2-B, Table 2-C, orTable 2-D by no more than about 50%. In other embodiments of theinvention, one or more compounds of formula I, I-P, I-E, I-P-E, I-P-Z,I-A, I-AP, I-A-E, I-AP-E, I-A-Z, I-AP-Z, I-B, I-BP, I-B-E, I-BP-E,I-B-Z, I-BP-Z, any one of I-1 through I-109, II, II-E, II-Z, II-A,II-A-E, II-A-Z, II-B, II-B-E, II-B-Z, any one of II-1 through II-23, IV,and any one of IV-1 through IV-10, but excluding compound I-1-Z, isadministered to a subject or patient in an amount sufficient to inhibitSSAO enzyme activity (whether the enzyme activity is due either tosoluble SSAO enzyme or membrane-bound VAP-1 protein, or due to both)and/or inhibit binding to VAP-1 protein by at least about 75% or morethan about 75%, while binding to a receptor or transporter (where thecompound may inhibit, antagonize, activate, or agonize the receptor ortransporter) listed in Table 2-A, Table 2-B, Table 2-C, or Table 2-D byno more than about 50%. In other embodiments of the invention, one ormore compounds of formula I, I-P, I-E, I-P-E, I-P-Z, I-A, I-AP, I-A-E,I-AP-E, I-A-Z, I-AP-Z, I-B, I-BP, I-B-E, I-BP-E, I-B-Z, I-BP-Z, any oneof I-1 through I-109, II, II-E, II-Z, II-A, II-A-E, II-A-Z, II-B,II-B-E, II-B-Z, any one of II-1 through II-23, IV, and any one of IV-1through IV-10, but excluding compound I-1-Z, is administered to asubject or patient in an amount sufficient to inhibit SSAO enzymeactivity (whether the enzyme activity is due either to soluble SSAOenzyme or membrane-bound VAP-1 protein, or due to both) and/or inhibitbinding to VAP-1 protein by at least about 50% or more than about 50%,while binding to a receptor or transporter (where the compound mayinhibit, antagonize, activate, or agonize the receptor or transporter)listed in Table 2-A, Table 2-B, Table 2-C, or Table 2-D by no more thanabout 25%. In other embodiments of the invention, one or more compoundsof formula I, I-P, I-E, I-P-E, I-P-Z, I-A, I-AP, I-A-E, I-AP-E, I-A-Z,I-AP-Z, I-B, I-BP, I-B-E, I-BP-E, I-B-Z, I-BP-Z, any one of I-1 throughI-109, II, II-E, II-Z, II-A, II-A-E, II-A-Z, II-B, II-B-E, II-B-Z, anyone of II-1 through II-23, IV, and any one of IV-1 through IV-10, butexcluding compound I-1-Z, is administered to a subject or patient in anamount sufficient to inhibit SSAO enzyme activity (whether the enzymeactivity is due either to soluble SSAO enzyme or membrane-bound VAP-1protein, or due to both) and/or inhibit binding to VAP-1 protein by atleast about 75% or more than about 75%, while binding to a receptor ortransporter (where the compound may inhibit, antagonize, activate, oragonize the receptor or transporter) listed in Table 2-A, Table 2-B,Table 2-C, or Table 2-D by no more than about 25%. In other embodimentsof the invention, one or more compounds of formula I, I-P, I-E, I-P-E,I-P-Z, I-A, I-AP, I-A-E, I-AP-E, I-A-Z, I-AP-Z, I-B, I-BP, I-B-E,I-BP-E, I-B-Z, I-B P-Z, any one of I-1 through I-109, II, II-E, II-Z,II-A, II-A-E, II-A-Z, II-B, II-B-E, II-B-Z, any one of II-1 throughII-23, IV, and any one of IV-1 through IV-10, but excluding compoundI-1-Z, is administered to a subject or patient in an amount sufficientto inhibit SSAO enzyme activity (whether the enzyme activity is dueeither to soluble SSAO enzyme or membrane-bound VAP-1 protein, or due toboth) and/or inhibit binding to VAP-1 protein by at least about 75% ormore than about 75%, while binding to a receptor or transporter (wherethe compound may inhibit, antagonize, activate, or agonize the receptoror transporter) listed in Table 2-A, Table 2-B, Table 2-C, or Table 2-Dby no more than about 10%. In other embodiments of the invention, one ormore compounds of formula I, I-P, I-E, I-P-E, I-P-Z, I-A, I-AP, I-A-E,I-AP-E, I-A-Z, I-AP-Z, I-B, I-BP, I-B-E, I-BP-E, I-B-Z, I-BP-Z, any oneof I-1 through I-109, II, II-E, II-Z, II-A, II-A-E, II-A-Z, II-B,II-B-E, II-B-Z, any one of II-1 through II-23, IV, and any one of IV-1through IV-10, but excluding compound I-1-Z, is administered to asubject or patient in an amount sufficient to inhibit SSAO enzymeactivity (whether the enzyme activity is due either to soluble SSAOenzyme or membrane-bound VAP-1 protein, or due to both) and/or inhibitbinding to VAP-1 protein by at least about 90% or more than about 90%,while binding to a receptor or transporter (where the compound mayinhibit, antagonize, activate, or agonize the receptor or transporter)listed in Table 2-A, Table 2-B, Table 2-C, or Table 2-D by no more thanabout 10%. In any of the foregoing embodiments, any one, any five, anyten, or all of the receptors and transporters listed may be selected asthe receptor or transporter which falls at or below the level specifiedfor binding, inhibiting, antagonizing, activating, or agonizing. In anyof the foregoing embodiments, the binding can be measured by an assaysuch as a competitive binding assay. In any of the foregoingembodiments, the binding can be measured by the procedures listed inTable 2 and Table 3.

In other embodiments, the invention embraces unit dosage formulations ofone or more compounds of formula I, I-P, I-E, I-P-E, I-P-Z, I-A, I-AP,I-A-E, I-AP-E, I-A-Z, I-AP-Z, I-B, I-BP, I-B-E, I-BP-E, I-B-Z, I-BP-Z,any one of I-1 through I-109, II, II-E, II-Z, II-A, II-A-E, II-A-Z,II-B, II-B-E, II-B-Z, any one of II-1 through II-23, IV, and any one ofIV-1 through IV-10, but excluding compound I-1-Z, which, whenadministered to a subject, is sufficient to inhibit SSAO enzyme activity(whether the enzyme activity is due either to soluble SSAO enzyme ormembrane-bound VAP-1 protein, or due to both) and/or inhibit binding toVAP-1 protein by at least about 50% or more than about 50%, whilebinding to a receptor or transporter (where the compound may inhibit,antagonize, activate, or agonize the receptor or transporter) listed inTable 2-A, Table 2-B, Table 2-C, or Table 2-D by no more than about 50%;or is sufficient to inhibit SSAO enzyme activity (whether the enzymeactivity is due either to soluble SSAO enzyme or membrane-bound VAP-1protein, or due to both) and/or inhibit binding to VAP-1 protein by atleast about 75% or more than about 75%, while binding to a receptor ortransporter (where the compound may inhibit, antagonize, activate, oragonize the receptor or transporter) listed in Table 2-A, Table 2-B,Table 2-C, or Table 2-D by no more than about 50%; or is sufficient toinhibit SSAO enzyme activity (whether the enzyme activity is due eitherto soluble SSAO enzyme or membrane-bound VAP-1 protein, or due to both)and/or inhibit binding to VAP-1 protein by at least about 50% or morethan about 50%, while binding to a receptor or transporter (where thecompound may inhibit, antagonize, activate, or agonize the receptor ortransporter) listed in Table 2-A, Table 2-B, Table 2-C, or Table 2-D byno more than about 25%; or is sufficient to inhibit SSAO enzyme activity(whether the enzyme activity is due either to soluble SSAO enzyme ormembrane-bound VAP-1 protein, or due to both) and/or inhibit binding toVAP-1 protein by at least about 75% or more than about 75%, whilebinding to a receptor or transporter (where the compound may inhibit,antagonize, activate, or agonize the receptor or transporter) listed inTable 2-A, Table 2-B, Table 2-C, or Table 2-D by no more than about 25%;or is sufficient to inhibit SSAO enzyme activity (whether the enzymeactivity is due either to soluble SSAO enzyme or membrane-bound VAP-1protein, or due to both) and/or inhibit binding to VAP-1 protein by atleast about 75% or more than about 75%, while binding to a receptor ortransporter (where the compound may inhibit, antagonize, activate, oragonize the receptor or transporter) listed in Table 2-A, Table 2-B,Table 2-C, or Table 2-D by no more than about 10%; or is sufficient toinhibit SSAO enzyme activity (whether the enzyme activity is due eitherto soluble SSAO enzyme or membrane-bound VAP-1 protein, or due to both)and/or inhibit binding to VAP-1 protein by at least about 90% or morethan about 90%, while binding to a receptor or transporter (where thecompound may inhibit, antagonize, activate, or agonize the receptor ortransporter) listed in Table 2-A, Table 2-B, Table 2-C, or Table 2-D byno more than about 10%. In any of the foregoing embodiments, any one,any five, any ten, or all of the receptors and transporters listed maybe selected as the receptor or transporter which falls at or below thelevel specified for binding, inhibiting, antagonizing, activating, oragonizing. In any of the foregoing embodiments, the binding can bemeasured by an assay such as a competitive binding assay. In any of theforegoing embodiments, the binding can be measured by the procedureslisted in Table 2 and Table 3.

In other embodiments of the invention, one or more compounds of formulaI, I-P, I-E, I-P-E, I-P-Z, I-A, I-AP, I-A-E, I-AP-E, I-A-Z, I-AP-Z, I-B,I-BP, I-B-E, I-BP-E, I-B-Z, I-BP-Z, any one of I-1 through I-109, II,II-E, II-Z, II-A, II-A-E, II-A-Z, II-B, II-B-E, II-B-Z, any one of II-1through II-23, IV, and any one of IV-1 through IV-10 is administered toa subject or patient in an amount sufficient to inhibit SSAO enzymeactivity (whether the enzyme activity is due either to soluble SSAOenzyme or membrane-bound VAP-1 protein, or due to both) and/or inhibitbinding to VAP-1 protein by at least about 50% or more than about 50%,while binding to a receptor (where the compound may inhibit, antagonize,activate, or agonize the receptor) listed in Table 2-A, Table 2-B, orTable 2-C (with the proviso that the 5-HT_(1A) receptor is excluded) byno more than about 50%. In other embodiments of the invention, one ormore compounds of formula I, I-P, I-E, I-P-E, I-P-Z, I-A, I-AP, I-A-E,I-AP-E, I-A-Z, I-AP-Z, I-B, I-BP, I-B-E, I-BP-E, I-B-Z, I-BP-Z, any oneof I-1 through I-109, II, II-E, II-Z, II-A, II-A-E, II-A-Z, II-B,II-B-E, II-B-Z, any one of II-1 through II-23, IV, and any one of IV-1through IV-10 is administered to a subject or patient in an amountsufficient to inhibit SSAO enzyme activity (whether the enzyme activityis due either to soluble SSAO enzyme or membrane-bound VAP-1 protein, ordue to both) and/or inhibit binding to VAP-1 protein by at least about75% or more than about 75%, while binding to a receptor (where thecompound may inhibit, antagonize, activate, or agonize the receptor)listed in Table 2-A, Table 2-B, or Table 2-C (with the proviso that the5-HT_(1A) receptor is excluded) by no more than about 50%. In otherembodiments of the invention, one or more compounds of formula I, I-P,I-E, I-P-E, I-P-Z, I-A, I-AP, I-A-E, I-AP-E, I-A-Z, I-AP-Z, I-B, I-BP,I-B-E, I-BP-E, I-B-Z, I-BP-Z, any one of I-1 through I-109, II, II-E,II-Z, II-A, II-A-E, II-A-Z, II-B, II-B-E, II-B-Z, any one of II-1through II-23, IV, and any one of IV-1 through IV-10 is administered toa subject or patient in an amount sufficient to inhibit SSAO enzymeactivity (whether the enzyme activity is due either to soluble SSAOenzyme or membrane-bound VAP-1 protein, or due to both) and/or inhibitbinding to VAP-1 protein by at least about 90% or more than about 90%,while binding to a receptor (where the compound may inhibit, antagonize,activate, or agonize the receptor) listed in Table 2-A, Table 2-B, orTable 2-C (with the proviso that the 5-HT_(1A) receptor is excluded) byno more than about 50%. In other embodiments of the invention, one ormore compounds of formula I, I-P, I-E, I-P-E, I-P-Z, I-A, I-AP, I-A-E,I-AP-E, I-A-Z, I-AP-Z, I-B, I-BP, I-B-E, I-BP-E, I-B-Z, I-BP-Z, any oneof I-1 through I-109, II, II-E, II-Z, II-A, II-A-E, II-A-Z, II-B,II-B-E, II-B-Z, any one of II-1 through II-23, IV, and any one of IV-1through IV-10 is administered to a subject or patient in an amountsufficient to inhibit SSAO enzyme activity (whether the enzyme activityis due either to soluble SSAO enzyme or membrane-bound VAP-1 protein, ordue to both) and/or inhibit binding to VAP-1 protein by at least about50% or more than about 50%, while binding to a receptor (where thecompound may inhibit, antagonize, activate, or agonize the receptor)listed in Table 2-A, Table 2-B, or Table 2-C (with the proviso that the5-HT_(1A) receptor is excluded) by no more than about 30%. In otherembodiments of the invention, one or more compounds of formula I, I-P,I-E, I-P-E, I-P-Z, I-A, I-AP, I-A-E, I-AP-E, I-A-Z, I-AP-Z, I-B, I-BP,I-B-E, I-BP-E, I-B-Z, I-BP-Z, any one of I-1 through I-109, II, II-E,II-Z, II-A, II-A-E, II-A-Z, II-B, II-B-E, II-B-Z, any one of II-1through II-23, IV, and any one of IV-1 through IV-10 is administered toa subject or patient in an amount sufficient to inhibit SSAO enzymeactivity (whether the enzyme activity is due either to soluble SSAOenzyme or membrane-bound VAP-1 protein, or due to both) and/or inhibitbinding to VAP-1 protein by at least about 75% or more than about 75%,while binding to a receptor (where the compound may inhibit, antagonize,activate, or agonize the receptor) listed in Table 2-A, Table 2-B, orTable 2-C (with the proviso that the 5-HT_(1A) receptor is excluded) byno more than about 30%. In other embodiments of the invention, one ormore compounds of formula I, I-P, I-E, I-P-E, I-P-Z, I-A, I-AP, I-A-E,I-AP-E, I-A-Z, I-AP-Z, I-B, I-BP, I-B-E, I-BP-E, I-B-Z, I-BP-Z, any oneof I-1 through I-109, II, II-E, II-Z, II-A, II-A-E, II-A-Z, II-B,II-B-E, II-B-Z, any one of II-1 through II-23, IV, and any one of IV-1through IV-10 is administered to a subject or patient in an amountsufficient to inhibit SSAO enzyme activity (whether the enzyme activityis due either to soluble SSAO enzyme or membrane-bound VAP-1 protein, ordue to both) and/or inhibit binding to VAP-1 protein by at least about90% or more than about 90%, while binding to a receptor (where thecompound may inhibit, antagonize, activate, or agonize the receptor)listed in Table 2-A, Table 2-B, or Table 2-C (with the proviso that the5-HT_(1A) receptor is excluded) by no more than about 30%. In any of theforegoing embodiments, the compound can be compound I-1-Z. In any of theforegoing embodiments, any one, any five, any ten, or all of thereceptors listed may be selected as the receptor which falls at or belowthe level specified for binding, inhibiting, antagonizing, activating,or agonizing. In any of the foregoing embodiments, the binding can bemeasured by an assay such as a competitive binding assay. In any of theforegoing embodiments, the binding can be measured by the procedureslisted in Table 2 and Table 3.

In other embodiments, the invention embraces unit dosage formulations ofone or more compounds of formula I, I-P, I-E, I-P-E, I-P-Z, I-A, I-AP,I-A-E, I-AP-E, I-A-Z, I-AP-Z, I-B, I-BP, I-B-E, I-BP-E, I-B-Z, I-BP-Z,any one of I-1 through I-109, II, II-E, II-Z, II-A, II-A-E, II-A-Z,II-B, II-B-E, II-B-Z, any one of II-1 through II-23, IV, and any one ofIV-1 through IV-10 which, when administered to a subject, is sufficientto inhibit SSAO enzyme activity (whether the enzyme activity is dueeither to soluble SSAO enzyme or membrane-bound VAP-1 protein, or due toboth) and/or inhibit binding to VAP-1 protein by at least about 50% ormore than about 50%, while binding to a receptor (where the compound mayinhibit, antagonize, activate, or agonize the receptor) listed in Table2-A, Table 2-B, or Table 2-C (with the proviso that the 5-HT_(1A)receptor is excluded) by no more than about 50%. In other embodiments,the invention embraces unit dosage formulations of one or more compoundsof formula I, I-P, I-E, I-P-E, I-P-Z, I-A, I-AP, I-A-E, I-AP-E, I-A-Z,I-AP-Z, I-B, I-BP, I-B-E, I-BP-E, I-B-Z, I-BP-Z, any one of I-1 throughI-109, II, II-E, II-Z, II-A, II-A-E, II-A-Z, II-B, II-B-E, II-B-Z, anyone of II-1 through II-23, IV, and any one of IV-1 through IV-10 which,when administered to a subject, is sufficient to inhibit SSAO enzymeactivity (whether the enzyme activity is due either to soluble SSAOenzyme or membrane-bound VAP-1 protein, or due to both) and/or inhibitbinding to VAP-1 protein by at least about 75% or more than about 75%,while binding to a receptor (where the compound may inhibit, antagonize,activate, or agonize the receptor) listed in Table 2-A, Table 2-B, orTable 2-C (with the proviso that the 5-HT_(1A) receptor is excluded) byno more than about 50%. In other embodiments, the invention embracesunit dosage formulations of one or more compounds of formula I, I-P,I-E, I-P-E, I-P-Z, I-A, I-AP, I-A-E, I-AP-E, I-A-Z, I-AP-Z, I-B, I-BP,I-B-E, I-BP-E, I-B-Z, I-BP-Z, any one of I-1 through I-109, II, II-E,II-Z, II-A, II-A-E, II-A-Z, II-B, II-B-E, II-B-Z, any one of II-1through II-23, IV, and any one of IV-1 through IV-10 which, whenadministered to a subject, is sufficient to inhibit SSAO enzyme activity(whether the enzyme activity is due either to soluble SSAO enzyme ormembrane-bound VAP-1 protein, or due to both) and/or inhibit binding toVAP-1 protein by at least about 90% or more than about 90%, whilebinding to a receptor (where the compound may inhibit, antagonize,activate, or agonize the receptor) listed in Table 2-A, Table 2-B, orTable 2-C (with the proviso that the 5-HT_(1A) receptor is excluded) byno more than about 50%. In other embodiments, the invention embracesunit dosage formulations of one or more compounds of formula I, I-P,I-E, I-P-E, I-P-Z, I-A, I-AP, I-A-E, I-AP-E, I-A-Z, I-AP-Z, I-B, I-BP,I-B-E, I-BP-E, I-B-Z, I-BP-Z, any one of I-1 through I-109, II, II-E,II-Z, II-A, II-A-E, II-A-Z, II-B, II-B-E, II-B-Z, any one of II-1through II-23, IV, and any one of IV-1 through IV-10 which, whenadministered to a subject, is sufficient to inhibit SSAO enzyme activity(whether the enzyme activity is due either to soluble SSAO enzyme ormembrane-bound VAP-1 protein, or due to both) and/or inhibit binding toVAP-1 protein by at least about 50% or more than about 50%, whilebinding to a receptor (where the compound may inhibit, antagonize,activate, or agonize the receptor) listed in Table 2-A, Table 2-B, orTable 2-C (with the proviso that the 5-HT_(1A) receptor is excluded) byno more than about 30%. In other embodiments, the invention embracesunit dosage formulations of one or more compounds of formula I, I-P,I-E, I-P-E, I-P-Z, I-A, I-AP, I-A-E, I-AP-E, I-A-Z, I-AP-Z, I-B, I-BP,I-B-E, I-BP-E, I-B-Z, I-BP-Z, any one of I-1 through I-109, II, II-E,II-Z, II-A, II-A-E, II-A-Z, II-B, II-B-E, II-B-Z, any one of II-1through II-23, IV, and any one of IV-1 through IV-10 which, whenadministered to a subject, is sufficient to inhibit SSAO enzyme activity(whether the enzyme activity is due either to soluble SSAO enzyme ormembrane-bound VAP-1 protein, or due to both) and/or inhibit binding toVAP-1 protein by at least about 75% or more than about 75%, whilebinding to a receptor (where the compound may inhibit, antagonize,activate, or agonize the receptor) listed in Table 2-A, Table 2-B, orTable 2-C (with the proviso that the 5-HT_(1A) receptor is excluded) byno more than about 30%. In other embodiments, the invention embracesunit dosage formulations of one or more compounds of formula I, I-P,I-E, I-P-E, I-P-Z, I-A, I-AP, I-A-E, I-AP-E, I-A-Z, I-AP-Z, I-B, I-BP,I-B-E, I-BP-E, I-B-Z, I-BP-Z, any one of I-1 through I-109, II, II-E,II-Z, II-A, II-A-E, II-A-Z, II-B, II-B-E, II-B-Z, any one of II-1through II-23, IV, and any one of IV-1 through IV-10 which, whenadministered to a subject, is sufficient to inhibit SSAO enzyme activity(whether the enzyme activity is due either to soluble SSAO enzyme ormembrane-bound VAP-1 protein, or due to both) and/or inhibit binding toVAP-1 protein by at least about 90% or more than about 90%, whilebinding to a receptor (where the compound may inhibit, antagonize,activate, or agonize the receptor) listed in Table 2-A, Table 2-B, orTable 2-C (with the proviso that the 5-HT_(1A) receptor is excluded) byno more than about 30%. In any of the foregoing embodiments, thecompound can be compound I-1-Z. In any of the foregoing embodiments, anyone, any five, any ten, or all of the receptors listed may be selectedas the receptor which falls at or below the level specified for binding,inhibiting, antagonizing, activating, or agonizing. In any of theforegoing embodiments, the binding can be measured by an assay such as acompetitive binding assay. In any of the foregoing embodiments, thebinding can be measured by the procedures listed in Table 2 and Table 3.

In other embodiments of the invention, one or more compounds of formulaI, I-P, I-E, I-P-E, I-P-Z, I-A, I-AP, I-A-E, I-AP-E, I-A-Z, I-AP-Z, I-B,I-BP, I-B-E, I-BP-E, I-B-Z, I-BP-Z, any one of I-1 through I-109, II,II-E, II-Z, II-A, II-A-E, II-A-Z, II-B, II-B-E, II-B-Z, any one of II-1through II-23, IV, and any one of IV-1 through IV-10 is administered toa subject or patient in an amount sufficient to inhibit SSAO enzymeactivity (whether the enzyme activity is due either to soluble SSAOenzyme or membrane-bound VAP-1 protein, or due to both) and/or inhibitbinding to VAP-1 protein by at least about 50% or more than about 50%,while binding to the 5-HT_(1A) receptor, the dopamine transporter, orthe serotonin transporter by no more than about 75%, preferably no morethan about 50%, more preferably no more than about 30% (where thecompound may inhibit, antagonize, activate, or agonize the receptor ortransporter). In other embodiments of the invention, one or morecompounds of formula I, I-P, I-E, I-P-E, I-P-Z, I-A, I-AP, I-A-E,I-AP-E, I-A-Z, I-AP-Z, I-B, I-BP, I-B-E, I-BP-E, I-B-Z, I-BP-Z, any oneof I-1 through I-109, II, II-E, II-Z, II-A, II-A-E, II-A-Z, II-B,II-B-E, II-B-Z, any one of II-1 through II-23, IV, and any one of IV-1through IV-10 is administered to a subject or patient in an amountsufficient to inhibit SSAO enzyme activity (whether the enzyme activityis due either to soluble SSAO enzyme or membrane-bound VAP-1 protein, ordue to both) and/or inhibit binding to VAP-1 protein by at least about75% or more than about 75%, while binding to the 5-HT_(1A) receptor, thedopamine transporter, or the serotonin transporter by no more than about75%, preferably no more than about 50%, more preferably no more thanabout 30% (where the compound may inhibit, antagonize, activate, oragonize the receptor or transporter). In other embodiments of theinvention, one or more compounds of formula I, I-P, I-E, I-P-E, I-P-Z,I-A, I-AP, I-A-E, I-AP-E, I-A-Z, I-AP-Z, I-B, I-BP, I-B-E, I-BP-E,I-B-Z, I-BP-Z, any one of I-1 through I-109, II, II-E, II-Z, II-A,II-A-E, II-A-Z, II-B, II-B-E, II-B-Z, any one of II-1 through II-23, IV,and any one of IV-1 through IV-10 is administered to a subject orpatient in an amount sufficient to inhibit SSAO enzyme activity (whetherthe enzyme activity is due either to soluble SSAO enzyme ormembrane-bound VAP-1 protein, or due to both) and/or inhibit binding toVAP-1 protein by at least about 90% or more than about 90%, whilebinding to the 5-HT_(1A) receptor, the dopamine transporter, or theserotonin transporter by no more than about 75%, preferably no more thanabout 50%, more preferably no more than about 30% (where the compoundmay inhibit, antagonize, activate, or agonize the receptor ortransporter). In any of the foregoing embodiments, the compound can becompound I-1-Z. In any of the foregoing embodiments, any one, any two,any three, or all four of the receptors/transporters listed may beselected as the receptor/transporter which falls at or below the levelspecified for inhibiting, antagonizing, activating, or agonizing. In anyof the foregoing embodiments, the binding can be measured by an assaysuch as a competitive binding assay. In any of the foregoingembodiments, the binding can be measured by the procedures listed inTable 2 and Table 3.

In other embodiments, the invention embraces unit dosage formulations ofone or more compounds of formula I, I-P, I-E, I-P-E, I-P-Z, I-A, I-AP,I-A-E, I-AP-E, I-A-Z, I-AP-Z, I-B, I-BP, I-B-E, I-BP-E, I-B-Z, I-BP-Z,any one of I-1 through I-109, II, II-E, II-Z, II-A, II-A-E, II-A-Z,II-B, II-B-E, II-B-Z, any one of II-1 through II-23, IV, and any one ofIV-1 through IV-10 which, when administered to a subject, is sufficientto inhibit SSAO enzyme activity (whether the enzyme activity is dueeither to soluble SSAO enzyme or membrane-bound VAP-1 protein, or due toboth) and/or inhibit binding to VAP-1 protein by at least about 50% ormore than about 50%, while binding to the 5-HT_(1A) receptor, thedopamine transporter, or the serotonin transporter by no more than about75%, preferably no more than about 50%, more preferably no more thanabout 30% (where the compound may inhibit, antagonize, activate, oragonize the receptor or transporter). In other embodiments, theinvention embraces unit dosage formulations of one or more compounds offormula I, I-P, I-E, I-P-E, I-P-Z, I-A, I-AP, I-A-E, I-AP-E, I-A-Z,I-AP-Z, I-B, I-BP, I-B-E, I-BP-E, I-B-Z, I-BP-Z, any one of I-1 throughI-109, II, II-E, II-Z, II-A, II-A-E, II-A-Z, II-B, II-B-E, II-B-Z, anyone of II-1 through II-23, IV, and any one of IV-1 through IV-10 which,when administered to a subject, is sufficient to inhibit SSAO enzymeactivity (whether the enzyme activity is due either to soluble SSAOenzyme or membrane-bound VAP-1 protein, or due to both) and/or inhibitbinding to VAP-1 protein by at least about 75% or more than about 75%,while binding to the 5-HT_(1A) receptor, the doparnine transporter, orthe serotonin transporter by no more than about 75%, preferably no morethan about 50%, more preferably no more than about 30% (where thecompound may inhibit, antagonize, activate, or agonize the receptor ortransporter). In other embodiments, the invention embraces unit dosageformulations of one or more compounds of formula I, I-P, I-E, I-P-E,I-P-Z, I-A, I-AP, I-A-E, I-AP-E, I-A-Z, I-AP-Z, I-B, I-BP, I-B-E,I-BP-E, I-B-Z, I-BP-Z, any one of I-1 through I-109, II, II-E, II-Z,II-A, II-A-E, II-A-Z, II-B, II-B-E, II-B-Z, any one of II-1 throughII-23, IV, and any one of IV-1 through IV-10 which, when administered toa subject, is sufficient to inhibit SSAO enzyme activity (whether theenzyme activity is due either to soluble SSAO enzyme or membrane-boundVAP-1 protein, or due to both) and/or inhibit binding to VAP-1 proteinby at least about 90% or more than about 90%, while binding to the5-HT_(1A) receptor, the dopamine transporter, or the serotonintransporter by no more than about 75%, preferably no more than about50%, more preferably no more than about 30% (where the compound mayinhibit, antagonize, activate, or agonize the receptor or transporter).In any of the foregoing embodiments, the compound can be compound I-1-Z.In any of the foregoing embodiments, any one, any two, any three, or allfour of the receptors/transporters listed may be selected as thereceptor/transporter which falls at or below the level specified forinhibiting, antagonizing, activating, or agonizing. In any of theforegoing embodiments, the binding can be measured by an assay such as acompetitive binding assay. In any of the foregoing embodiments, thebinding can be measured by the procedures listed in Table 2 and Table 3.

In other embodiments of the invention, one or more compounds of formulaI, I-P, I-E, I-P-E, I-P-Z, I-A, I-AP, I-A-E, I-AP-E, I-A-Z, I-AP-Z, I-B,I-BP, I-B-E, I-BP-E, I-B-Z, I-BP-Z, any one of I-1 through I-109, II,II-E, II-Z, II-A, II-A-E, II-A-Z, II-B, II-B-E, II-B-Z, any one of II-1through II-23, IV, and any one of IV-1 through IV-10 is administered toa subject or patient in an amount sufficient to inhibit SSAO enzymeactivity (whether the enzyme activity is due either to soluble SSAOenzyme or membrane-bound VAP-1 protein, or due to both) and/or inhibitbinding to VAP-1 protein by at least about 50% or more than about 50%,while binding to the norepinephrine transporter by no more than about75%, preferably no more than about 50%, more preferably no more thanabout 30% (where the compound may inhibit, antagonize, activate, oragonize the transporter). In other embodiments of the invention, one ormore compounds of formula I, I-P, I-E, I-P-E, I-P-Z, I-A, I-AP, I-A-E,I-AP-E, I-A-Z, I-AP-Z, I-B, I-BP, I-B-E, I-BP-E, I-B-Z, I-BP-Z, any oneof I-1 through I-109, II, II-E, II-Z, II-A, II-A-E, II-A-Z, II-B,II-B-E, II-B-Z, any one of II-1 through II-23, IV, and any one of IV-1through IV-10 is administered to a subject or patient in an amountsufficient to inhibit SSAO enzyme activity (whether the enzyme activityis due either to soluble SSAO enzyme or membrane-bound VAP-1 protein, ordue to both) and/or inhibit binding to VAP-1 protein by at least about75% or more than about 75%, while binding to the norepinephrinetransporter by no more than about 75%, preferably no more than about50%, more preferably no more than about 30% (where the compound mayinhibit, antagonize, activate, or agonize the transporter). In otherembodiments of the invention, one or more compounds of formula I, I-P,I-E, I-P-E, I-P-Z, I-A, I-AP, I-A-E, I-AP-E, I-A-Z, I-AP-Z, I-B, I-BP,I-B-E, I-BP-E, I-B-Z, I-BP-Z, any one of I-1 through I-109, II, II-E,II-Z, II-A, II-A-E, II-A-Z, II-B, II-B-E, II-B-Z, any one of II-1through II-23, IV, and any one of IV-1 through IV-10 is administered toa subject or patient in an amount sufficient to inhibit SSAO enzymeactivity (whether the enzyme activity is due either to soluble SSAOenzyme or membrane-bound VAP-1 protein, or due to both) and/or inhibitbinding to VAP-1 protein by at least about 90% or more than about 90%,while binding to the norepinephrine transporter by no more than about75%, preferably no more than about 50%, more preferably no more thanabout 30% (where the compound may inhibit, antagonize, activate, oragonize the transporter). In any of the foregoing embodiments, thecompound can be compound I-1-Z. In any of the foregoing embodiments, thebinding can be measured by an assay such as a competitive binding assay.In any of the foregoing embodiments, the binding can be measured by theprocedures listed in Table 2 and Table 3.

In other embodiments, the invention embraces unit dosage formulations ofone or more compounds of formula I, I-P, I-E, I-P-E, I-P-Z, I-A, I-AP,I-A-E, I-AP-E, I-A-Z, I-AP-Z, I-B, I-BP, I-B-E, I-BP-E, I-B-Z, I-BP-Z,any one of I-1 through I-109, II, II-E, II-Z, II-A, II-A-E, II-A-Z,II-B, II-B-E, II-B-Z, any one of II-1 through II-23, IV, and any one ofIV-1 through IV-10 which, when administered to a subject, is sufficientto inhibit SSAO enzyme activity (whether the enzyme activity is dueeither to soluble SSAO enzyme or membrane-bound VAP-1 protein, or due toboth) and/or inhibit binding to VAP-1 protein by at least about 50% ormore than about 50%, while binding to the norepinephrine transporter byno more than about 75%, preferably no more than about 50%, morepreferably no more than about 30% (where the compound may inhibit,antagonize, activate, or agonize the transporter). In other embodiments,the invention embraces unit dosage formulations of one or more compoundsof formula I, I-P, I-E, I-P-E, I-P-Z, I-A, I-AP, I-A-E, I-AP-E, I-A-Z,I-AP-Z, I-B, I-BP, I-B-E, I-BP-E, I-B-Z, I-BP-Z, any one of I-1 throughI-109, II, II-E, II-Z, II-A, II-A-E, II-A-Z, II-B, I-B-E, II-B-Z, anyone of II-1 through II-23, IV, and any one of IV-1 through IV-10 which,when administered to a subject, is sufficient to inhibit SSAO enzymeactivity (whether the enzyme activity is due either to soluble SSAOenzyme or membrane-bound VAP-1 protein, or due to both) and/or inhibitbinding to VAP-1 protein by at least about 75% or more than about 75%,while binding to the norepinephrine transporter by no more than about75%, preferably no more than about 50%, more preferably no more thanabout 30% (where the compound may inhibit, antagonize, activate, oragonize the transporter). In other embodiments, the invention embracesunit dosage formulations of one or more compounds of formula I, I-P,I-E, I-P-E, I-P-Z, I-A, I-AP, I-A-E, I-AP-E, I-A-Z, I-AP-Z, I-B, I-BP,I-B-E, I-BP-E, I-B-Z, I-BP-Z, any one of I-1 through I-109, II, II-E,II-Z, II-A, II-A-E, II-A-Z, II-B, II-B-E, II-B-Z, any one of II-1through II-23, IV, and any one of IV-1 through IV-10 which, whenadministered to a subject, is sufficient to inhibit SSAO enzyme activity(whether the enzyme activity is due either to soluble SSAO enzyme ormembrane-bound VAP-1 protein, or due to both) and/or inhibit binding toVAP-1 protein by at least about 90% or more than about 90%, whilebinding to the norepinephrine transporter by no more than about 75%,preferably no more than about 50%, more preferably no more than about30% (where the compound may inhibit, antagonize, activate, or agonizethe transporter). In any of the foregoing embodiments, the compound canbe compound I-1-Z. In any of the foregoing embodiments, the binding canbe measured by an assay such as a competitive binding assay. In any ofthe foregoing embodiments, the binding can be measured by the procedureslisted in Table 2 and Table 3.

In another embodiment, the present invention relates to methods of usingone or more compounds of formula I, I-P, I-E, I-P-E, I-P-Z, I-A, I-AP,I-A-E, I-AP-E, I-A-Z, I-AP-Z, I-B, I-B P, I-B-E, I-B P-E, I-B-Z, I-BP-Z,any one of I-1 through I-109, II, II-E, II-Z, II-A, II-A-E, II-A-Z,II-B, II-B-E, II-B-Z, any one of II-1 through II-23, IV, and any one ofIV-1 through IV-10 to treat or prevent inflammation or immune disorders.In another embodiment, the present invention relates to methods of usingone or more compounds of formula I, I-P, I-E, I-P-E, I-P-Z, I-A, I-AP,I-A-E, I-AP-E, I-A-Z, I-AP-Z, I-B, I-BP, I-B-E, I-BP-E, I-B-Z, I-BP-Z,any one of I-1 through I-109, II, II-E, II-Z, II-A, II-A-E, II-A-Z,II-B, II-B-E, II-B-Z, any one of II-1 through II-23, IV, and any one ofIV-1 through IV-10 to suppress or reduce inflammation, or to suppress orreduce an inflammatory response. In another embodiment, the presentinvention relates to methods of treating or preventing inflammation, byadministering one or more compounds of formula I, I-P, I-E, I-P-E,I-P-Z, I-A, I-AP, I-A-E, I-AP-E, I-A-Z, I-AP-Z, I-B, I-BP, I-B-E,I-BP-E, I-B-Z, I-BP-Z, any one of I-1 through I-109, II, II-E, II-Z,II-A, II-A-E, II-A-Z, II-B, II-B-E, II-B-Z, any one of II-1 throughII-23, IV, and any one of IV-1 through IV-10 in a therapeuticallyeffective amount, or in an amount sufficient to treat or preventinflammation. In another embodiment, the present invention relates tomethods of treating or preventing immune or autoimmune disorders, byadministering one or more compounds of formula I, I-P, I-E, I-P-E,I-P-Z, I-A, I-AP, I-A-E, I-AP-E, I-A-Z, I-AP-Z, I-B, I-BP, I-B-E,I-BP-E, I-B-Z, I-BP-Z, any one of I-1 through I-109, II, II-E, II-Z,II-A, II-A-E, II-A-Z, II-B, II-B-E, II-B-Z, any one of II-1 throughII-23, IV, and any one of IV-1 through IV-10 in a therapeuticallyeffective amount, or in an amount sufficient to treat or prevent theimmune or autoimmune disorder.

In another embodiment, the inflammatory disease or immune disorder to betreated or prevented by one or more compounds of formula I, I-P, I-E,I-P-E, I-P-Z, I-A, I-AP, I-A-E, I-AP-E, I-A-Z, I-AP-Z, I-B, I-BP, I-B-E,I-BP-E, I-B-Z, I-BP-Z, any one of I-1 through I-109, II, II-E, II-Z,II-A, II-A-E, II-A-Z, II-B, II-B-E, II-B-Z, any one of II-1 throughII-23, IV, and any one of IV-1 through IV-10 of the present invention isselected from the group consisting of multiple sclerosis (includingchronic multiple sclerosis); synovitis; systemic inflammatory sepsis;inflammatory bowel diseases; Crohn's disease; ulcerative colitis;Alzheimer's disease; vascular dementia; atherosclerosis; rheumatoidarthritis; juvenile rheumatoid arthritis; pulmonary inflammatoryconditions; asthma; skin inflammatory conditions and diseases; contactdermatitis; liver inflammatory and autoimmune conditions; autoimmunehepatitis; primary biliary cirrhosis; sclerosing cholangitis; autoimmunecholangitis; alcoholic liver disease; Type I diabetes and/orcomplications thereof; Type II diabetes and/or complications thereof;atherosclerosis; chronic heart failure; congestive heart failure;ischemic diseases such as stroke and/or complications thereof; andmyocardial infarction and/or complications thereof. In anotherembodiment, the inflammatory disease or immune disorder to be treated orprevented by the present invention is multiple sclerosis (includingchronic multiple sclerosis). In another embodiment, the inflammatorydisease or immune disorder to be treated or prevented by the presentinvention is stroke or the inflammatory complications resulting fromstroke.

A compound of formula I, I-P, I-E, I-P-E, I-P-Z, I-A, I-AP, I-A-E,I-AP-E, I-A-Z, I-AP-Z, I-B, I-BP, I-B-E, I-BP-E, I-B-Z, I-BP-Z, any oneof I-1 through I-109, II, II-E, II-Z, II-A, II-A-E, II-A-Z, II-B,II-B-E, II-B-Z, any one of II-1 through II-23, IV, and any one of IV-1through IV-10 as described above can be administered singly in atherapeutically effective amount. A compound of formula compound offormula I, I-P, I-E, I-P-E, I-P-Z, I-A, I-AP, I-A-E, I-AP-E, I-A-Z,I-AP-Z, I-B, I-BP, I-B-E, I-BP-E, I-B-Z, I-BP-Z, any one of I-1 throughI-109, II, II-E, II-Z, II-A, II-A-E, II-A-Z, II-B, II-B-E, II-B-Z, anyone of II-1 through II-23, IV, and any one of IV-1 through IV-10 asdescribed above can be administered with one or more additionalcompounds of formula I, I-P, I-E, I-P-E, I-P-Z, I-A, I-AP, I-A-E,I-AP-E, I-A-Z, I-AP-Z, I-B, I-BP, I-B-E, I-BP-E, I-B-Z, I-BP-Z, any oneof I-1 through I-109, II, II-E, II-Z, II-A, II-A-E, II-A-Z, II-B,II-B-E, II-B-Z, any one of II-1 through II-23, IV, and any one of IV-1through IV-10, in a therapeutically effective amount. When administeredin combination, the compounds can be administered in amounts that wouldbe therapeutically effective were the compounds to be administeredsingly. Alternatively, when administered in combination, any or all ofcompounds can be administered in amounts that would not betherapeutically effective were the compounds to be administered singly,but which are therapeutically effective in combination. One or morecompounds of formula I, I-P, I-E, I-P-E, I-P-Z, I-A, I-AP, I-A-E,I-AP-E, I-A-Z, I-AP-Z, I-B, I-BP, I-B-E, I-BP-E, I-B-Z, I-BP-Z, any oneof I-1 through I-109, II, II-E, II-Z, II-A, II-A-E, II-A-Z, II-B,II-B-E, II-B-Z, any one of II-1 through II-23, IV, and any one of IV-1through IV-10 can also be administered with other compounds not includedin formulas I, I-P, I-E, I-P-E, I-P-Z, I-A, I-AP, I-A-E, I-AP-E, I-A-Z,I-AP-Z, I-B, I-BP, I-B-E, I-BP-E, I-B-Z, I-BP-Z, any one of I-1 throughI-109, II, II-E, II-Z, II-A, II-A-E, II-A-Z, II-B, II-B-E, II-B-Z, anyone of II-1 through II-23, IV, and any one of IV-1 through IV-10; thecompounds can be administered in amounts that are therapeuticallyeffective when used as single drugs, or in amounts which are nottherapeutically effective as single drugs, but which are therapeuticallyeffective in combination. Also provided are pharmaceutically acceptablecompositions comprising a therapeutically effective amount of one ormore of the compounds disclosed herein or a therapeutically effectivecombination of two or more of the compounds disclosed herein, includingthe compounds of formula I, I-P, I-E, I-P-E, I-P-Z, I-A, I-AP, I-A-E,I-AP-E, I-A-Z, I-AP-Z, I-B, I-BP, I-B-E, I-BP-E, I-B-Z. I-BP-Z, any oneof I-1 through I-109, II, II-E, II-Z, II-A, II-A-E, II-A-Z, II-B,II-B-E, II-B-Z, any one of II-1 through II-23, IV, and any one of IV-1through IV-10 above, and a pharmaceutically acceptable carrier; andhuman unit dosages thereof.

A compound of formula I, I-P, I-E, I-P-E, I-P-Z, I-A, I-AP, I-A-E,I-AP-E, I-A-Z, I-AP-Z, I-B, I-BP, I-B-E, I-BP-E, I-B-Z, I-BP-Z, any oneof I-1 through I-109, II, II-E, II-Z, II-A, II-A-E, II-A-Z, II-B,II-B-E, II-B-Z, any one of II-1 through II-23, IV, and any one of IV-1through IV-10 as described above can be prepared as an isolatedpharmaceutical composition, and administered as an isolatedpharmaceutical composition in conjunction with vehicles or otherisolated compounds. That is, a compound of formula I, I-P, I-E, I-P-E,I-P-Z, I-A, I-AP, I-A-E, I-AP-E, I-A-Z, I-AP-Z, I-B, I-BP, I-B-E,I-BP-E, I-B-Z, I-B P-Z, any one of I-1 through I-109, II, II-E, II-Z,II-A, II-A-E, II-A-Z, II-B, II-B-E, II-B-Z, any one of II-1 throughII-23, IV, and any one of IV-1 through IV-10 as described above can beisolated from other compounds (e.g., a compound which is discovered in alibrary screening assay can be purified out of the library, orsynthesized de novo as a single compound). The degree of purificationcan be 90%, 95%, 99%, or whatever percentage of purity is required forpharmaceutical use of the compound. The isolated compound can then becombined with pharmaceutically acceptable vehicles, or can be combinedwith one or more isolated compounds of formula I, I-P, I-E, I-P-E,I-P-Z, I-A, I-AP, I-A-E, I-AP-E, I-A-Z, I-AP-Z, I-B, I-BP, I-B-E, I-BP-E, I-B-Z, I-BP-Z, any one of I-1 through I-109, II, II-E, II-Z, II-A,II-A-E, II-A-Z, II-B, II-B-E, II-B-Z, any one of II-1 through II-23, IV,and any one of IV-1 through IV-10, or with another therapeuticsubstance. A compound of formula I, I-P, I-E, I-P-E, I-P-Z, I-A, I-AP,I-A-E, I-AP-E, I-A-Z, I-AP-Z, I-B, I-BP, I-B-E, I-BP-E, I-B-Z, I-BP-Z,any one of I-1 through I-109, II, II-E, II-Z, II-A, II-A-E, II-A-Z,II-B, II-B-E, II-B-Z, any one of II-1 through II-23, IV, and any one ofIV-1 through IV-10 as described above can be administered orally, in apharmaceutical human unit dosage formulation. The pharmaceutical humanunit dosage formulation can contain a therapeutically effective amountof a compound of formula I, I-P, I-E, I-P-E, I-P-Z, I-A, I-AP, I-A-E,I-AP-E, I-A-Z, I-AP-Z, I-B, I-BP, I-B-E, I-BP-E, I-B-Z, I-BP-Z, any oneof I-1 through I-109, II, II-E, II-Z, II-A, II-A-E, II-A-Z, II-B,II-B-E, II-B-Z, any one of II-1 through II-23, IV, and any one of IV-1through IV-10 for treatment or prevention of any disease disclosedherein.

In another embodiment, the invention embraces one or more compounds offormula I, I-P, I-E, I-P-E, I-P-Z, I-A, I-AP, I-A-E, I-AP-E, I-A-Z,I-AP-Z, I-B, I-BP, I-B-E, I-BP-E, I-B-Z, I-BP-Z, or any one of I-1through I-109, such as I-1-Z, I-2-Z, or I-2-E, for use in therapy. Inanother embodiment, the invention embraces one or more compounds offormula I, I-P, I-E, I-P-E, I-P-Z, I-A, I-AP, I-A-E, I-AP-E, I-A-Z,I-AP-Z, I-B, I-BP, I-B-E, I-BP-E, I-B-Z, I-BP-Z, I or any one of I-1through I-109, such as I-1-Z, I-2-Z, or I-2-E, for manufacture of amedicament for treatment or prevention of inflammatory diseases. Inanother embodiment, the invention embraces one or more compounds offormula I, I-P, I-E, I-P-E, I-P-Z, I-A, I-AP, I-A-E, I-AP-E, I-A-Z,I-AP-Z, I-B, I-BP, I-B-E, I-BP-E, I-B-Z, I-BP-Z, or any one of I-1through I-109, such as I-1-Z, I-2-Z, or I-2-E, for manufacture of amedicament for treatment or prevention of immune or autoimmune diseases.In another embodiment, the invention embraces one or more compounds offormula I, I-P, I-E, I-P-E, I-P-Z, I-A, I-AP, I-A-E, I-AP-E, I-A-Z,I-AP-Z, I-B, I-BP, I-B-E, I-BP-E, I-B-Z, I-BP-Z, or any one of I-1through I-109, such as I-1-Z, I-2-Z, or 1-2-E, for manufacture of amedicament for treatment or prevention of multiple sclerosis or chronicmultiple sclerosis. In another embodiment, the invention embraces one ormore compounds of formula I, I-P, I-E, I-P-E, I-P-Z, I-A, I-AP, I-A-E,I-AP-E, I-A-Z, I-AP-Z, I-B, I-BP, I-B-E, I-BP-E, I-B-Z, I-BP-Z, I or anyone of I-1 through I-109, such as I-1 -Z, I-2-Z, or I-2-E, formanufacture of a medicament for treatment or prevention of ischemicdiseases (such as stroke) or the sequelae of ischemic diseases.

In another embodiment, the invention embraces one or more compounds offormula II, II-E, II-Z, II-A, II-A-E, II-A-Z, II-B, I-B-E, II-B-Z, I-1,II-2, II-3, II-4, II-5, II-6, II-7, II-8, II-9, II-10, II-11, II-12,II-13, II-14, II-15, II-16, II-17, II-18, II-19, II-20, II-21, II-22, orII-23, such as II-1-E, for use in therapy. In another embodiment, theinvention embraces one or more compounds of formula II, II-E, II-Z,II-A, II-A-E, II-A-Z, II-B, II-B-E, II-B-Z, II-1, II-2, II-3, II-4,II-5, II-6, II-7, II-8, II-9, II-10, II-11, II-12, II-13, II-14, II-15,II-16, II-17, II-18, II-19, II-20, II-21, II-22, or II-23, such asII-2-E, for manufacture of a medicament for treatment or prevention ofinflammatory diseases. In another embodiment, the invention embraces oneor more compounds of formula II, II-E, II-Z, II- A, II-A-E, II-A-Z,II-B, II-B-E, II-B-Z, II-1, II-2, II-3, II-4, II-5, II-6, II-7, II-8,II-9, II-10, II-11, II-12, II-13, II-14, II-15, II-16, II-17, II-18,II-19, II-20, II-21, II-22, or II-23, such as II-1-E, for manufacture ofa medicament for treatment or prevention of immune or autoimmunediseases. In another embodiment, the invention embraces one or morecompounds of formula II, II-E, II-Z, II-A, II-A-E, II-A-Z, II-B, II-B-E,II-B-Z, II-1, II-2, II-3, II-4, II-5, II-6, II-7, II-8, II-9, II-10,II-11, II-12, II-13, II-14, II-15, II-16, II-17, II-18, II-19, II-20,II-21, II-22, or II-23, such as II-1-E, for manufacture of a medicamentfor treatment or prevention of multiple sclerosis or chronic multiplesclerosis. In another embodiment, the invention embraces one or morecompounds of formula II, II-E, II-Z, II-A, II-A-E, II-A-Z, II-B, II-B-E,II-B-Z, II-1, II-2, II-3, II-4, II-5, II-6, II-7, II-8, II-9, II-10,II-11, II-12, II-13, II-14, II-15, II-16, II-17, II-18, II-19, II-20,II-21, II-22, II-23, or II-24, such as II-1-E, for manufacture of amedicament for treatment or prevention of ischemic diseases (such asstroke) or the sequelae of ischemic diseases.

In another embodiment, the invention embraces one or more compounds offormula IV-1, IV-2, IV-3, IV-4, IV-5, IV-6, IV-7, IV-8, IV-9, or IV-10,for use in therapy. In another embodiment, the invention embraces one ormore compounds of formula IV-1, IV-2, IV-3, IV-4, IV-5, IV-6, IV-7,IV-8, IV-9, or IV-10, for manufacture of a medicament for treatment orprevention of inflammatory diseases. In another embodiment, theinvention embraces one or more compounds of formula IV-1, IV-2, IV-3,IV-4, IV-5, IV-6, IV-7, IV-8, IV-9, or IV-10, for manufacture of amedicament for treatment or prevention of immune or autoimmune diseases.In another embodiment, the invention embraces one or more compounds offormula IV-1, IV-2, IV-3, IV-4, IV-5, IV-6, IV-7, IV-8, IV-9, or IV-10,for manufacture of a medicament for treatment or prevention of multiplesclerosis or chronic multiple sclerosis. In another embodiment, theinvention embraces one or more compounds of formula IV-1, IV-2, IV-3,IV-4, IV-5, IV-6, IV-7, IV-8, IV-9, or IV-10, for manufacture of amedicament for treatment or prevention of ischemic diseases (such asstroke) or the sequelae of ischemic diseases.

For all of the compounds, and methods using the compounds, disclosedherein, the compounds can be admixed with a pharmaceutically acceptableexcipient or pharmaceutically acceptable carrier.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts the effect of Compound II-1-E on carrageenan-induced ratpaw edema.

FIG. 2 depicts the effect of Compound II-1-E on body weight (FIG. 2A)and survival (FIG. 2B) of mice with ulcerative colitis.

FIG. 3 depicts the effect of Compound II-1-E on development of acuteexperimental autoimmune encephalomyelitis.

FIG. 4 depicts the effect of Compound I-1-Z on development of murineanti-collagen-induced arthritis.

FIG. 5 depicts the effect of Compound I-1-Z on carrageenan-induced ratpaw edema.

FIG. 6 depicts the effect of Compound I-2-Z on carrageenan-induced ratpaw edema.

FIG. 7 depicts the dose responsive effect of Compound I-1-Z oncarrageenan-induced rat paw edema.

FIG. 8 depicts the effect of therapeutic dosing with Compound I-1-Z oncarrageenan-induced rat paw edema.

FIG. 9 depicts the effect of therapeutic dosing with Compound I-1-Z onanti-collagen antibody-induced arthritis.

FIG. 10 depicts the effect of Compound I-1-Z on cell trafficking.

FIG. 11 depicts the determination of ED50 of Compound I-1-Z for rat lungSSAO.

FIG. 12 depicts the effect of low doses of Compound I-1-Z onanti-collagen antibody-induced arthritis.

FIG. 13 depicts the effect of low doses of Compound I-1-Z oncarrageenan-induced rat paw edema.

FIG. 14 depicts the effect of doses of Compound I-1-Z on LPS-inducedlung inflammation.

FIG. 15 depicts the effect of doses of Compound I-1-Z oncollagen-induced arthritis. Panel A shows clinical arthritis scores,while Panel B shows percent incidence.

FIG. 16 depicts the effect of route of administration of Compound I-1-Zon cell trafficking.

MODES FOR CARRYING OUT THE INVENTION

The present invention relates to various compounds which are useful forinhibiting SSAO enzyme activity (where the enzyme activity is due eitherto soluble SSAO enzyme or membrane-bound VAP-1 protein, or due to both)and/or inhibition of binding to membrane-bound VAP-1 protein. Thepresent invention also relates to methods of using various compounds toinhibit SSAO enzyme activity (where the enzyme activity is due either tosoluble SSAO enzyme or membrane-bound VAP-1 protein, or due to both)and/or inhibit binding to VAP-1 protein. The present invention alsorelates to methods of using various compounds to treat or preventinflammation or immune disorders, and to reduce or suppress inflammationor inflammatory responses.

Compounds for use in the invention can be assayed for SSAO inhibitoryactivity by the protocol in the examples below. It is preferable to usecompounds which specifically inhibit SSAO over monoamine oxidase. Thespecificity of the compounds for SSAO inhibitory activity versus MAO-Aand MAO-B inhibitory activity can be assayed by the protocol in theexamples below. Compounds for use in the invention have an inhibitoryactivity (IC₅₀) against SSAO of about <1 μM, more preferably of about100 nM, and more preferably of about 10 nM. Preferably, compounds foruse in the invention also have a specificity for SSAO versus MAO-A ofabout 10-fold, greater than about 10-fold, about 100-fold, greater thanabout 100-fold, about 500-fold, greater than about 500-fold, about1,000-fold, greater than about 1000-fold, about 5,000-fold, or greaterthan about 5000-fold (where specificity for SSAO versus MAO-A is definedas the ratio of the IC₅₀ of a compound for MAO-A to the IC₅₀ of the samecompound for SSAO; that is, a compound with an IC₅₀ of 10 μM for MAO-Aand an IC₅₀ of 20 nM for SSAO has a specificity of 500 for SSAO versusMAO-A). Compounds for use in the invention also have a specificity forSSAO versus MAO-B of about 10-fold, greater than about 10-fold, about100-fold, greater than about 100-fold, about 500-fold, greater thanabout 500-fold, about 1,000-fold, greater than about 1000-fold, about5,000-fold, or greater than about 5000-fold (where specificity for SSAOversus MAO-B is defined as the ratio of the IC₅₀ of a compound for MAO-Bto the IC₅₀ of the same compound for SSAO). Table 1 below providesexperimental values for several of the compounds for use in theinvention.

The term “inhibit binding to VAP-1 protein” is meant to indicateinhibition (which can include partial to complete inhibition) of bindingbetween, for example, a cell expressing the SSAO/VAP-1 protein on itssurface, and a binding partner of SSAO/VAP-1 protein. Such bindingoccurs, for example, when a cell expressing the SSAO/VAP-1 protein onits surface, such as a high endothelial cell (HEC) interacts withanother cell expressing a binding partner of SSAO/VAP-1 protein, such asa leukocyte. Thus “inhibit binding to VAP-1 protein” embraces inhibitionof adhesion between a cell expressing the SSAO/VAP-1 protein on itssurface, and another cell expressing a binding partner of SSAO/VAP-1protein. Such adhesion events include, for example, cell rolling. Asthis disclosure (including the examples) clearly indicates, suchinhibition can occur either in vitro or in vivo. Binding can beinhibited by about 5% or by greater than about 5%, about 10% or bygreater than about 10%, about 20% or by greater than about 20%, about30% or by greater than about 30%, about 40% or by greater than about40%, about 50% or by greater than about 50%, about 60% or by greaterthan about 60%, about 70% or by greater than about 70%, about 80% or bygreater than about 80%, about 90% or by greater than about 90%, or about95% or by greater than about 95%.

The invention includes all salts of the compounds described herein, aswell as methods of using such salts of the compounds. The invention alsoincludes all non-salt forms of any salt of a compound named herein, aswell as other salts of any salt of a compound named herein. In oneembodiment, the salts of the compounds comprise pharmaceuticallyacceptable salts. Pharmaceutically acceptable salts are those saltswhich retain the biological activity of the free compounds and which canbe administered as drugs or pharmaceuticals to humans and/or animals.The desired salt of a basic compound may be prepared by methods known tothose of skill in the art by treating the compound with an acid.Examples of inorganic acids include, but are not limited to,hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, andphosphoric acid. Examples of organic acids include, but are not limitedto, formic acid, acetic acid, propionic acid, glycolic acid, pyruvicacid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaricacid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelicacid, sulfonic acids, and salicylic acid. Salts of basic compounds withamino acids, such as aspartate salts and glutamate salts, can also beprepared. The desired salt of an acidic compound can be prepared bymethods known to those of skill in the art by treating the compound witha base. Examples of inorganic salts of acid compounds include, but arenot limited to, alkali metal and alkaline earth salts, such as sodiumsalts, potassium salts, magnesium salts, and calcium salts; ammoniumsalts; and aluminum salts. Examples of organic salts of acid compoundsinclude, but are not limited to, procaine, dibenzylamine,N-ethylpiperidine, N,N′-dibenzylethylenediamine, and triethylaminesalts. Salts of acidic compounds with amino acids, such as lysine salts,can also be prepared.

The invention includes all stereoisomers of the compounds referred to inthe above formulas, including enantiomers and diastereomers. Theinvention includes all enantiomers of any chiral compound disclosed, ineither substantially pure levorotatory or dextrorotatory form, or in aracemic mixture, or in any ratio of enantiomers. The invention includesany diastereomers of the compounds referred to in the above formulas indiastereomerically pure form and in the form of mixtures in all ratios.For compounds disclosed as an E isomer, the invention also includes theZ isomer; for compounds disclosed as the Z isomer, the invention alsoincludes the E isomer. The invention also includes all solvates of thecompounds referred to in the above formulas, including all hydrates ofthe compounds referred to in the above formulas. The invention alsoincludes all polymorphs, including crystalline and non-crystalline formsof the compounds referred to in the above formulas. The invention alsoincludes all salts of the compounds referred to in the above formulas,particularly pharmaceutically-acceptable salts. Metabolites and prodrugsof the compounds referred to in the above formulas are also embraced bythe invention. In all uses of the compounds of the above formulasdisclosed herein, the invention also includes use of any or all of thestereochemical, enantiomeric, diastereomeric, E or Z forms, solvates,hydrates, polymorphic, crystalline, non-crystalline, salt,pharmaceutically acceptable salt, metabolite and prodrug variations ofthe compounds as described.

Unless stereochemistry is explicitly indicated in a chemical structureor chemical name, the chemical structure or chemical name is intended toembrace all possible stereoisomers of the compound depicted. Forexample, the compound I-1 is intended to embrace compounds I-1 -E andI-1-Z.

The term “alkyl” refers to saturated aliphatic and alicyclic groupsincluding straight-chain, branched-chain, cyclic groups, andcombinations thereof, having the number of carbon atoms specified, or ifno number is specified, having up to 12 carbon atoms. “Straight-chainalkyl” or “linear alkyl” groups refers to alkyl groups that are neithercyclic nor branched, commonly designated as “n-alkyl” groups. Examplesof alkyl groups include, but are not limited to, groups such as methyl,ethyl, n-propyl, isopropyl, butyl, n-butyl, isobutyl, sec-butyl,t-butyl, pentyl, n-pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl,dodecyl, neopentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,and adamantyl. Cycloalkyl groups can consist of one ring, including, butnot limited to, groups such as cycloheptyl, or multiple fused rings,including, but not limited to, groups such as adamantyl or norbornyl.

“Substituted alkyl” refers to alkyl groups substituted with one or moresubstituents including, but not limited to, groups such as halogen(fluoro, chloro, bromo, and iodo), alkoxy, acyloxy, amino, hydroxyl,mercapto, carboxy, benzyloxy, phenyl, benzyl, cyano, nitro, thioalkoxy,carboxaldehyde, carboalkoxy and carboxamide, or a functionality that canbe suitably blocked, if necessary for purposes of the invention, with aprotecting group. Examples of substituted alkyl groups include, but arenot limited to, —CF₃, —CF₂—CF₃, and other perfluoro and perhalo groups;—CH₂—OH; —CH₂CH₂CH(NH₂)CH₃, etc.

The term “alkenyl” refers to unsaturated aliphatic and alicyclic groupsincluding straight-chain (linear), branched-chain, cyclic groups, andcombinations thereof, having the number of carbon atoms specified, or ifno number is specified, having up to 12 carbon atoms, which contain atleast one double bond (—C═C—). Examples of alkenyl groups include, butare not limited to, —CH₂—CH═CH—CH₃; and —CH₂—CH₂-cyclohexenyl, where theethyl group can be attached to the cyclohexenyl moiety at any availablecarbon valence. The term “alkynyl” refers to unsaturated aliphatic andalicyclic groups including straight-chain (linear), branched-chain,cyclic groups, and combinations thereof, having the number of carbonatoms specified, or if no number is specified, having up to 12 carbonatoms, which contain at least one triple bond (—C≡C—). “Hydrocarbonchain” or “hydrocarbyl” refers to any combination of straight-chain,branched-chain, or cyclic alkyl, alkenyl, or alkynyl groups, and anycombination thereof. “Substituted alkenyl,” “substituted alkynyl,” and“substituted hydrocarbon chain” or “substituted hydrocarbyl” refer tothe respective group substituted with one or more substituents,including, but not limited to, groups such as halogen, alkoxy, acyloxy,amino, hydroxyl, mercapto, carboxy, benzyloxy, phenyl, benzyl, cyano,nitro, thioalkoxy, carboxaldehyde, carboalkoxy and carboxamide, or afunctionality that can be suitably blocked, if necessary for purposes ofthe invention, with a protecting group.

“Aryl” or “Ar” refers to an aromatic carbocyclic group having a singlering (including, but not limited to, groups such as phenyl) or two ormore condensed rings (including, but not limited to, groups such asnaphthyl or anthryl), and includes both unsubstituted and substitutedaryl groups. Aryls, unless otherwise specified, contain from 6 to 12carbon atoms in the ring portion. A preferred range for aryls is from 6to 10 carbon atoms in the ring portion. “Substituted aryls” refers toaryls substituted with one or more substituents, including, but notlimited to, groups such as alkyl, alkenyl, alkynyl, hydrocarbon chains,halogen, alkoxy, acyloxy, amino, hydroxyl, mercapto, carboxy, benzyloxy,phenyl, benzyl, cyano, nitro, thioalkoxy, carboxaldehyde, carboalkoxyand carboxamide, or a functionality that can be suitably blocked, ifnecessary for purposes of the invention, with a protecting group.“Aralkyl” designates an alkyl-substituted aryl group, where any aryl canattached to the alkyl; the alkyl portion is a straight or branched chainof 1 to 6 carbon atoms, preferably the alkyl chain contains 1 to 3carbon atoms. When an aralkyl group is indicated as a substituent, thearalkyl group can be connected to the remainder of the molecule at anyavailable valence on either its alkyl moiety or aryl moiety; e.g., thetolyl aralkyl group can be connected to the remainder of the molecule byreplacing any of the five hydrogens on the aromatic ring moiety with theremainder of the molecule, or by replacing one of the alpha-hydrogens onthe methyl moiety with the remainder of the molecule. Preferably, thearalkyl group is connected to the remainder of the molecule via thealkyl moiety.

A preferred aryl group is phenyl, which can be substituted orunsubstituted. Preferred substituents for substituted phenyl groups arelower alkyl (—C₁-C₄ alkyl), or a halogen (chlorine (—Cl), bromine (—Br),iodine (—I), or fluorine (—F); preferred halogen substituents for phenylgroups are chlorine and fluorine), hydroxy (—OH), or lower alkoxy(—C₁-C₄ alkoxy), such as methoxy, ethoxy, propyloxy (propoxy) (eithern-propoxy or i-propoxy), and butoxy (either n-butoxy, i-butoxy,sec-butoxy, or tert-butoxy); a preferred alkoxy substituent is methoxy.Substituted phenyl groups preferably have one or two substituents; morepreferably, one substituent.

“Heteroalkyl,” “heteroalkenyl,” and “heteroalkynyl” refer to alkyl,alkenyl, and alkynyl groups, respectively, that contain the number ofcarbon atoms specified (or if no number is specified, having up to 12carbon atoms) which contain one or more heteroatoms as part of the main,branched, or cyclic chains in the group. Heteroatoms include, but arenot limited to, N, S, O, and P; N and O are preferred. Heteroalkyl,heteroalkenyl, and heteroalkynyl groups may be attached to the remainderof the molecule either at a heteroatom (if a valence is available) or ata carbon atom. Examples of heteroalkyl groups include, but are notlimited to, groups such as —O—CH₃, —CH₂—O—CH₃, —CH₂—CH₂—O—CH₃,—S—CH₂—CH₂—CH₃, —CH₂—CH(CH₃)—S—CH₃, —CH₂—CH₂—NH—CH₂—CH₂—,1-ethyl-6-propylpiperidino, and morpholino. Examples of heteroalkenylgroups include, but are not limited to, groups such as—CH═CH—NH—CH(CH₃)—CH₂—. “Heteroaryl” or “HetAr” refers to an aromaticcarbocyclic group having a single ring (including, but not limited to,examples such as pyridyl, imidazolyl, thiophene, or furyl) or two ormore condensed rings (including, but not limited to, examples such asindolizinyl or benzothienyl) and having at least one hetero atom,including, but not limited to, heteroatoms such as N, O, P, or S, withinthe ring. Unless otherwise specified, heteroalkyl, heteroalkenyl,heteroalkynyl, and heteroaryl groups have between one and fiveheteroatoms and between one and twelve carbon atoms. “Substitutedheteroalkyl,” “substituted heteroalkenyl,” “substituted heteroalkynyl,”and “substituted heteroaryl” groups refer to heteroalkyl, heteroalkenyl,heteroalkynyl, and heteroaryl groups substituted with one or moresubstituents, including, but not limited to, groups such as alkyl,alkenyl, alkynyl, benzyl, hydrocarbon chains, halogen, alkoxy, acyloxy,amino, hydroxyl, mercapto, carboxy, benzyloxy, phenyl, benzyl, cyano,nitro, thioalkoxy, carboxaldehyde, carboalkoxy and carboxamide, or afunctionality that can be suitably blocked, if necessary for purposes ofthe invention, with a protecting group. Examples of such substitutedheteroalkyl groups include, but are not limited to, piperazine,substituted at a nitrogen or carbon by a phenyl or benzyl group, andattached to the remainder of the molecule by any available valence on acarbon or nitrogen, —NH—SO₂-phenyl, —NH—(C═O)O-alkyl,—NH—(C═O)O-alkyl-aryl, and —NH—(C═O)-alkyl. If chemically possible, theheteroatom(s) and/or the carbon atoms of the group can be substituted.The heteroatom(s) can also be in oxidized form, if chemically possible.

The term “alkoxy” as used herein refers to an alkyl, alkenyl, alkynyl,or hydrocarbon chain linked to an oxygen atom and having the number ofcarbon atoms specified, or if no number is specified, having up to 12carbon atoms. Examples of alkoxy groups include, but are not limited to,groups such as methoxy, ethoxy, propyloxy (propoxy) (either n-propoxy ori-propoxy), and butoxy (either n-butoxy, i-butoxy, sec-butoxy, ortert-butoxy). The groups listed in the preceding sentence are preferredalkoxy groups; a particularly preferred alkoxy substituent is methoxy.

The terms “halo” and “halogen” as used herein refer to the Group VIIaelements (Group 17 elements in the 1990 IUPAC Periodic Table, IUPACNomenclature of Inorganic Chemistry, Recommendations 1990) and includeCl, Br, F and I substituents. Preferred halogen substituents are Cl andF.

“Protecting group” refers to a chemical group that exhibits thefollowing characteristics: 1) reacts selectively with the desiredfunctionality in good yield to give a protected substrate that is stableto the projected reactions for which protection is desired; 2) isselectively removable from the protected substrate to yield the desiredfunctionality; and 3) is removable in good yield by reagents compatiblewith the other functional group(s) present or generated in suchprojected reactions. Examples of suitable protecting groups can be foundin Greene et al. (1991) Protective Groups in Organic Synthesis, 3rd Ed.(John Wiley & Sons, Inc., New York). Amino protecting groups include,but are not limited to, mesitylenesulfonyl (Mts), benzyloxycarbonyl (CBzor Z), t-butyloxycarbonyl (Boc), t-butyldimethylsilyl (TBS or TBDMS),9-fluorenylmethyloxycarbonyl (Fmoc), tosyl, benzenesulfonyl, 2-pyridylsulfonyl, or suitable photolabile protecting groups such as6-nitroveratryloxy carbonyl (Nvoc), nitropiperonyl,pyrenylmethoxycarbonyl, nitrobenzyl,α-,α-dimethyl-dimethoxybenzyloxycarbonyl (DDZ),5-bromo-7-nitroindolinyl, and the like. Hydroxyl protecting groupsinclude, but are not limited to, Fmoc, TBS, photolabile protectinggroups (such as nitroveratryl oxymethyl ether (Nvom)), Mom (methoxymethyl ether), and Mem (methoxy ethoxy methyl ether), NPEOC(4-nitrophenethyloxycarbonyl) and NPEOM(4-nitrophenethyloxymethyloxycarbonyl).

General Synthetic Methods

A method of synthesizing compounds of formula I, I-P, I-E, I-Z, I-P-E,I-P-Z, I-A, I-AP, I-A-E, I-AP-E, I-A-Z, I-AP-Z, I-B, I-BP, I-B-E,I-BP-E, I-B-Z, and/or I-BP-Z, is by adapting the synthesis for compoundsI-1-E and I-1-Z:

which is shown below in Scheme 1:

The ω-phenyl alkyl bromide compound was used to form the Grignardreagent based on conditions well known in the art by reacting ω-phenylalkyl bromide with Mg metal. The Grignard reagent was coupled withBoc-protected glycine Weinreb amide in the presence of MeMgBr to giveketone derivative III-30. Wittig reaction of the ketone with theappropriate reagent provided Z and E isomers, which were then separatedusing column chromatography. Upon removing the Boc protecting groupunder acidic conditions, the final compounds are obtained as the TFAsalts, which were easily converted to the HCl salts of I-1-E and I-1-Z.

Intermediate compound III-30 is of formulas III, III-A, and III-B, andthe synthesis shown in Scheme I for III-30 exemplifies one method ofsynthesizing compounds of any one of formulas III, III-A, and III-B.

If the appropriate co-phenyl alkyl bromide is not commerciallyavailable, the bromide can be synthesized from the corresponding acid asexemplified in the synthesis of 4-trifluoromethylphenylethyl bromide:

which is shown below in Scheme 2:

Thus, ω-phenyl alkyl acid was first converted to its correspondingmethyl ester under conditions well known in the art. The methyl esterwas then be reduced, either at room temperature with lithium aluminumhydride, or at −78° C. with DIBAL, to provide the corresponding alcohol.The alcohol was then converted to the desired bromide in the presence ofCBr₄ and PPh₃.

Another method of synthesizing compounds of formula I, I-P, I-E, I-Z,I-P-E, I-P-Z, I-A, I-AP, I-A-E, I-AP-E, I-A-Z, I-AP-Z, I-B, I-BP, I-B-E,I-BP-E, I-B-Z, and/or I-BP-Z is by an alternate synthesis to theprotected amino ketone intermediate, as exemplified by the synthesis ofcompound III-17:

which is shown below in Scheme 3:

A solution of carboxylate starting material was treated with oxalylchloride and DMF to form an acid chloride intermediate. The crudeproduct was then treated with trimethylsilyldiazomethane followed by HBrin acetic acid to yield 3-(3-Trifluoromethylphenyl)-2-oxopropyl bromide.The α-bromo ketone was then subjected to sodium azide to yield3-(3-Trifluoromethylphenyl)-2-oxopropylazide, followed by hydrogenationto generate 3-(3-Trifluoromethylphenyl)-2-oxopropylamine hydrochloride.The amino ketone was then treated with Boc anhydride under basicconditions to yield the protected amino ketone III-17. The intermediateIII-17 was then subjected the Wittig conditions and deprotectiondescribed in Scheme 1 to generate the desired product.

Intermediate compound III-17 is of formula III, III-A, and III-B, andits synthesis shown in Scheme I exemplifies one method of synthesizingcompounds of any one of formulas III, III-A, and III-B.

Synthesizing compounds of formula I, I-P, I-E, I-Z, I-P-E, I-P-Z, I-A,I-AP, I-A-E, I-AP-E, I-A-Z, I-AP-Z, I-B, I-BP, I-B-E, I-BP-E, I-B-Z,and/or I-BP-Z where X is O or S can be accomplished by adapting thesynthesis described above wherein starting material carboxylate isproperly substituted with an oxygen or sulfur atom. Preparation ofcarboxylate starting material where X is O or S is described below:

Thus a properly substituted phenol or thiophenol is treated with base,followed by addition of bromoacetic acid. The reaction mixture isacidified and the product extracted with EtOAc and recrystallized fromEtOAc/hexane. The O/S substituted carboxylate product is then used togenerate the appropriately protected amino ketone under conditionsdescribed in Scheme 3 followed by subsequent Wittig treatment anddeprotection described in Scheme 1 to yield the desired product.

A method of synthesizing compounds of formula II, II-E, II-Z, II-A,II-A-E, II-A-Z, II-B, II-B-E, and/or II-B-Z, is by adapting thesynthesis for compounds II-1-E and II-1-Z:

which is shown below in Scheme 4:

The carboxylate starting material was esterified under acidic conditionsto generate the methyl ester, which was then reduced with DIBAL-H to theα-phenyl alkyl aldehyde. The aldehyde was reacted with the ylidgenerated from the reaction of triethyl 2-fluoro-2-phosphonoacetate andNaH resulting in the ethyl ester E & Z isomers. The cis and transisomers were separated using column chromatography and each isomerindividually reduced using DIBAL to yield. The resulting alcoholproduced was then coupled with phthalimide under Mitsunobu conditions togive the phthalimide derivative. The phthalimide protecting group wasremoved with MeNH₂ to generate II-1-E and II-1-Z followed byacidification to give the final compound as the HCl salt. Note that thefinal compounds in Scheme 4 are the hydrochloride salts of II-1-E andII-1-Z.

Removal of the phthalimide protecting group in Scheme 4 may also beimmediately followed by treatment with HCl to form the salt form of thedesired product without isolation of the free amine intermediate.

For compounds where the substituent R₈ is other than hydrogen, thecorresponding ketone can be used as the starting material. Thus, forexample, in the synthesis depicted in Scheme 4, the compound R—CH₂—CHO(where R is 3-fluoro-5-trifluoromethyl) would be replaced by a compoundof the formula R—CH₂—C(═O)—R₈. If the corresponding ketone is notcommercially available, it can be produced by reacting the correspondingcarboxylic acid with two equivalents of the appropriate alkyllithiumreagent (R₈—Li) or via other methods known to the skilled artisan.

A method of synthesizing compounds of formula II, II-E, II-Z, II-A,II-A-E, II-A-Z, II-B, II-B-E, and/or II-B-Z, where X is O or S can beaccomplished by adapting the synthesis of compound II-19:

which is shown below in Scheme 5:

A solution of ethyl glycolate and imidazole in DMF was cooled andtreated with tert-butyldiphenyl silane chloride to generate the acetatefollowed by reduction to the aldehyde with DIBAL. The aldehyde wasexposed to triethyl 2-fluoro-2-phosphonacetate and isopropylmagnesiumchloride in THF to form the fluoro substituted intermediate, thenreduced to the primary alcohol by treatment with DIBAL and coupled with(E)-N-t-Butoxycarbonyl-N-(ethoxyoxoacetyl)-4-(tert-butyldiphenylsilanyloxy)-2-fluoro-2-butenylamine.The product was as treated with tetrabutylammonium fluoride trihydrateto form alcohol (E)-tert-butyl 2-fluoro-4-hydroxybut-2-enylcarbamate.The intermediate was coupled to the desired substituted phenol withtriphenyl phosphine and DIAD in THF to generate the Boc-protectedprecursor, followed by standard acid treatment to remove the Bocprotecting group forming the final product II-19.

Intermediate (E)-tert-butyl 2-fluoro-4-hydroxybut-2-enylcarbamate may becoupled to any number of substituted phenols, thiophenols, heterocyclichydroxyls, or heterocyclic thiols using the methods of Scheme 5 tosynthesize compounds of formula II, II-E, II-Z, II-A, II-A-E, II-A-Z,II-B, II-B-E, and/or II-B-Z, where X is O or S.

Methods of Use

The compounds discussed herein can be used in a variety of manners. Onesuch use is in treatment or prevention of inflammation, inflammatorydiseases, inflammatory responses, and certain other diseases, asdescribed in more detail below under “Treatment and Prevention ofDiseases.” Other uses include inhibiting SSAO enzyme activity and/orVAP-1 binding activity or VAP-1 amine oxidase activity, both in vivo andin vitro. An example of in vitro use of the compounds is use in assays,such as conventional assays or high-throughput screening assays.Compounds containing nitro (NO₂), bromo (Br), and/or iodo (I) groups canbe used for treatment and prevention, but should be evaluated carefullyfor toxicity due to the presence of the nitro, bromo, and/or iodogroups. These compounds can also be useful intermediate compounds (e.g.,the nitro group can be reduced to an amino group in a syntheticpathway).

Treatment and Prevention of Diseases

Compounds discussed herein are useful for treating or preventinginflammation and inflammatory conditions, and for treating or preventingimmune and autoimmune disorders. The compounds are also useful fortreating or preventing one or more of a variety of diseases caused by orcharacterized by inflammation or immune disorders. Thus the compoundscan be used to treat or prevent diseases caused by inflammation, and canalso be used to treat or prevent diseases which cause inflammation. Thecompounds are used for treatment or prevention in mammals, preferablyhumans. “Treating” a disease with the compounds discussed herein isdefined as administering one or more of the compounds discussed herein,with or without additional therapeutic agents, in order to palliate,ameliorate, stabilize, reverse, slow, delay, reduce, or eliminate eitherthe disease or one or more symptoms of the disease, or to retard or stopthe progression of the disease or of one or more symptoms of thedisease. To “prevent” a disease means to suppress the occurrence of adisease or symptoms of a disease before its clinical manifestation.Prevention or suppression can be partial or total. It should be notedthat the use of the compounds and/or methods for treatment and the useof the compounds and/or methods for prevention need not be mutuallyexclusive. “Therapeutic use” of the compounds discussed herein isdefined as using one or more of the compounds discussed herein to treator prevent a disease, as defined above. A “therapeutically effectiveamount” of a compound is an amount of the compound, which, whenadministered to a subject, is sufficient to treat, prevent, reduce, oreliminate either the disease or one or more symptoms of the disease, orto retard the progression of the disease or of one or more symptoms ofthe disease, or to reduce the severity of the disease or of one or moresymptoms of the disease. A “therapeutically effective amount” can begiven in one or more administrations.

The subjects undergoing treatment or preventive therapy with thecompounds and methods of the invention include vertebrates, preferablymammals, more preferably humans.

Diseases which can be treated or prevented with the compound and methodsof the invention include inflammation, inflammatory responses,inflammatory diseases and immune disorders. It should be noted thatinflammatory diseases can be caused by immune disorders, and that immunedisorders are often accompanied by inflammation, and therefore bothinflammation and immune disorders may be treated or preventedsimultaneously by the compounds and methods of the invention. Diseaseswhich can be treated or prevented with the compounds and methods of theinvention include, but are not limited to, multiple sclerosis (includingchronic multiple sclerosis); synovitis; systemic inflammatory sepsis;inflammatory bowel diseases; Crohn's disease; ulcerative colitis;Alzheimer's disease; atherosclerosis; rheumatoid arthritis; juvenilerheumatoid arthritis; pulmonary inflammatory conditions; asthma; skininflammatory conditions and diseases; contact dermatitis; liverinflammatory and autoimmune conditions; autoimmune hepatitis; primarybiliary cirrhosis; sclerosing cholangitis; autoimmune cholangitis;alcoholic liver disease; Type I diabetes and/or complications thereof;Type II diabetes and/or complications thereof; atherosclerosis; ischemicdiseases such as stroke and/or complications thereof; and myocardialinfarction. In another embodiment, the inflammatory disease or immunedisorder to be treated or prevented by the present invention is multiplesclerosis. In another embodiment, the inflammatory disease or immunedisorder to be treated or prevented by the present invention is chronicmultiple sclerosis. In another embodiment, the inflammatory disease orimmune disorder to be treated or prevented by the present invention isthe inflammatory complications resulting from stroke.

Modes of Administration

The compounds described for use in the present invention can beadministered to a mammalian, preferably human, subject via any routeknown in the art, including, but not limited to, those disclosed herein.Methods of administration include but are not limited to, intravenous,oral, intraarterial, intramuscular, topical, via inhalation (e.g. asmists or sprays), via nasal mucosa, subcutaneous, transdermal,intraperitoneal, gastrointestinal, and directly to a specific oraffected organ. Oral administration is a preferred route ofadministration. The compounds described for use herein can beadministered in the form of tablets, pills, powder mixtures, capsules,granules, injectables, creams, solutions, suppositories, emulsions,dispersions, food premixes, and in other suitable forms. The compoundscan also be administered in liposome formulations. Additional methods ofadministration are known in the art.

The compounds can be administered in prodrug form. Prodrugs arederivatives of the compounds which are themselves relatively inactive,but which convert into the active compound when introduced into thesubject in which they are used, by a chemical or biological process invivo, such as an enzymatic conversion. Suitable prodrug formulationsinclude, but are not limited to, peptide conjugates of the compounds ofthe invention and esters of compounds of the inventions. Furtherdiscussion of suitable prodrugs is provided in H. Bundgaard, Design ofProdrugs, New York: Elsevier, 1985; in R. Silverman, The OrganicChemistry of Drug Design and Drug Action, Boston: Elsevier, 2004; in R.L. Juliano (ed.), Biological Approaches to the Controlled Delivery ofDrugs (Annals of the New York Academy of Sciences, v. 507), New York:New York Academy of Sciences, 1987; and in E. B. Roche (ed.), Design ofBiopharmaceutical Properties Through Prodrugs and Analogs (Symposiumsponsored by Medicinal Chemistry Section, APhA Academy of PharmaceuticalSciences, November 1976 national meeting, Orlando, Fla.), Washington:The Academy, 1977. It should be noted that in all of the syntheticschemes presented, the penultimate compounds can be used as prodrugs.That is, the Boc-protected, and similarly protected or derivatizedcompounds (which appear in the synthetic pathway prior to the desiredactive compound and/or salt of the desired compound) can be used asprodrugs.

The compounds of the present invention may be administered in aneffective amount within the dosage range of about 0.1 μg/kg to about 300mg/kg, or within about 1.0 μg/kg to about 40 mg/kg body weight, orwithin about 1.0 μg/kg to about 20 mg/kg body weight, preferably betweenabout 1.0 μg/kg to about 10 mg/kg body weight. Compounds of the presentinvention may be administered in a single daily dose, or the total dailydosage may be administered in divided dosage of two, three or four timesdaily.

The pharmaceutical dosage form which contains the compounds describedherein is conveniently admixed with a non-toxic pharmaceutical organiccarrier or a non-toxic pharmaceutical inorganic carrier; that is, with apharmaceutically acceptable excipient or pharmaceutically acceptablecarrier. Typical pharmaceutically-acceptable carriers include, forexample, mannitol, urea, dextrans, lactose, potato and maize starches,magnesium stearate, talc, vegetable oils, polyalkylene glycols, ethylcellulose, poly(vinylpyrrolidone), calcium carbonate, ethyl oleate,isopropyl myristate, benzyl benzoate, sodium carbonate, gelatin,potassium carbonate, silicic acid, and other conventionally employedacceptable carriers. The pharmaceutical dosage form can also containnon-toxic auxiliary substances such as emulsifying, preserving, orwetting agents, and the like. A suitable carrier is one which does notcause an intolerable side effect, but which allows the compound(s) toretain its pharmacological activity in the body. Formulations forparenteral and nonparenteral drug delivery are known in the art and areset forth in Remington: The Science and Practice of Pharmacy, 20thEdition, Lippincott, Williams & Wilkins (2000). Solid forms, such astablets, capsules and powders, can be fabricated using conventionaltableting and capsule-filling machinery, which is well known in the art.Solid dosage forms, including tablets and capsules for oraladministration in unit dose presentation form, can contain any number ofadditional non-active ingredients known to the art, including suchconventional additives as excipients; desiccants; colorants; bindingagents, for example syrup, acacia, gelatin, sorbitol, tragacanth, orpolyvinylpyrollidone; fillers, for example lactose, sugar, maize-starch,calcium phosphate, sorbitol or glycine; tableting lubricants, forexample magnesium stearate, talc, polyethylene glycol or silica;disintegrants, for example potato starch; or acceptable wetting agentssuch as sodium lauryl sulfate. The tablets can be coated according tomethods well known in standard pharmaceutical practice. Liquid forms foringestion can be formulated using known liquid carriers, includingaqueous and non-aqueous carriers such as sterile water, sterile saline,suspensions, oil-in-water and/or water-in-oil emulsions, and the like.Liquid formulations can also contain any number of additional non-activeingredients, including colorants, fragrance, flavorings, viscositymodifiers, preservatives, stabilizers, and the like. For parenteraladministration, the compounds for use in the invention can beadministered as injectable dosages of a solution or suspension of thecompound in a physiologically acceptable diluent or sterile liquidcarrier such as water, saline, or oil, with or without additionalsurfactants or adjuvants. An illustrative list of carrier oils wouldinclude animal and vegetable oils (e.g., peanut oil, soy bean oil),petroleum-derived oils (e.g., mineral oil), and synthetic oils. Ingeneral, for injectable unit doses, sterile liquids such as water,saline, aqueous dextrose and related sugar solutions, and ethanol andglycol solutions such as propylene glycol or polyethylene glycol arepreferred liquid carriers.

The pharmaceutical unit dosage chosen is preferably fabricated andadministered to provide a concentration of drug in the blood, tissues,organs, or other targeted region of the body which is therapeuticallyeffective for use in treatment of one or more of the diseases describedherein. The optimal effective concentration of the compounds of theinvention can be determined empirically and will depend on the type andseverity of the disease, route of administration, disease progressionand health, mass and body area of the patient. Such determinations arewithin the skill of one in the art. The compounds for use in theinvention can be administered as the sole active ingredient, or can beadministered in combination with another active ingredient.

Kits

The invention also provides articles of manufacture and kits containingmaterials useful for treating or preventing diseases such asinflammatory diseases, autoimmune diseases, multiple sclerosis(including chronic multiple sclerosis); synovitis; systemic inflammatorysepsis; inflammatory bowel diseases; Crohn's disease; ulcerativecolitis; Alzheimer's disease; atherosclerosis; rheumatoid arthritis;juvenile rheumatoid arthritis; pulmonary inflammatory conditions;asthma; skin inflammatory conditions and diseases; contact dermatitis;liver inflammatory and autoimmune conditions; autoimmune hepatitis;primary biliary cirrhosis; sclerosing cholangitis; autoimmunecholangitis; alcoholic liver disease; Type I diabetes and/orcomplications thereof; Type II diabetes and/or complications thereof;atherosclerosis; ischemic diseases such as stroke and/or complicationsthereof; and myocardial infarction; or for inhibiting SSAO enzymeactivity (whether the enzyme activity is due either to soluble SSAOenzyme or membrane-bound VAP-1 protein, or due to both) and/orinhibiting binding to VAP-1 protein. The article of manufacturecomprises a container with a label. Suitable containers include, forexample, bottles, vials, and test tubes. The containers may be formedfrom a variety of materials such as glass or plastic. The containerholds a composition having an active agent which is effective fortreating or preventing diseases or for inhibiting SSAO or VAP-1 enzymeactivity or binding to VAP-1 protein. The active agent in thecomposition is one or more of the compounds of formula I, I-P, I-E,I-P-E, I-P-Z, I-A, I-AP, I-A-E, I-AP-E, I-A-Z, I-AP-Z, I-B, I-BP, I-B-E,I-BP-E, I-B-Z, I-BP-Z, any one of I-1 through I-109, II, II-E, II-Z,II-A, II-A-E, II-A-Z, II-B, II-B-E, II-B-Z, any one of II-1 throughII-23, IV, or any one of IV-1 through IV-10. The label on the containerindicates that the composition is used for treating or preventingdiseases such as inflammatory or autoimmune diseases, or for inhibitingSSAO or VAP-1 enzyme activity or binding to VAP-1 protein, and may alsoindicate directions for either in vivo or in vitro use, such as thosedescribed above.

The invention also provides kits comprising any one or more of thecompounds of formula I, I-P, I-E, I-P-E, I-P-Z, I-A, I-AP, I-A-E,I-AP-E, I-A-Z, I-AP-Z, I-B, I-BP, I-B-E, I-BP-E, I-B-Z, I-BP-Z, any oneof I-1 through I-109, II, II-E, II-Z, II-A, II-A-E, II-A-Z, II-B,II-B-E, II-B-Z, any one of II-1 through II-23, IV, or any one of IV-1through IV-10. In some embodiments, the kit of the invention comprisesthe container described above. In other embodiments, the kit of theinvention comprises the container described above and a second containercomprising a buffer. It may further include other materials desirablefrom a commercial and user standpoint, including other buffers,diluents, filters, needles, syringes, and package inserts withinstructions for performing any methods described herein (such asmethods for treating or preventing autoimmune or inflammatory diseases,and methods for inhibiting SSAO or VAP-1 enzyme activity or binding toVAP-1 protein).

In other aspects, the kits may be used for any of the methods describedherein, including, for example, to treat an individual with autoimmuneor inflammatory disease, such as multiple sclerosis or ischemic disease(such as stroke) and the sequelae thereof.

The disclosures of all publications, patents, patent applications andpublished patent applications referred to herein by an identifyingcitation are hereby incorporated herein by reference in their entirety.

The invention will be further understood by the following nonlimitingexamples. It should be noted that, while the compounds are typicallydescribed as salts, the disclosure expressly includes the non-salt formsof the compounds, as well as any other salt of the compound.

EXAMPLES

The syntheses of the compounds are depicted in Schemes I, II, III and IVabove, as well as in the following examples.

Example 1 Synthesis of Compounds of Formula III tert-butyl4-(4-methoxyphenyl)-2-oxobutylcarbamate (III-30)

To a cooled suspension of N-(tert-butoxycarbonyl) glycineN′-methoxy-N′-methylamide (1.86 g, 8.53 mmol) in THF (15 mL) at −15° C.under N₂ was added dropwise a solution of MeMgBr in toluene/THF (1.4M,5.97 mL, 8.36 mmol, 0.98 eq.). To the resulting clear solution was addeda solution of 4-methoxyphenylethyl magnesium bromide Grignard reagent inTHF (0.5 M, 21.5 mL, 10.7 mmol, 1.26 eq). The resulting mixture wasstirred at −15° C. and allowed to warm gradually to room temperature fora 4 hours period, at which time TLC showed the reaction was completed.The reaction mixture was cooled in an ice-bath, and a solution ofaqueous HCl (1N, 20 mL) was added, followed by ethyl acetate (60 mL).The layers were separated, and the aqueous layer was extracted withethyl acetate (2×30 mL). The combined organic layers were washed withbrine (30 mL), dried (Na₂SO₄), filtered, and concentrated in vacuo togive an oil, which was then purified by flash column chromatography(silica gel, 10% EtOAc/hexane) to give the ketone product. (2.28 g, 91%)¹H NMR (CDCl₃, 300 MHz) δ 1.44 (s, 9H), 2.72 (t, J=7.5 Hz, 2H), 2.88 (t,J=7.5 Hz, 2H), 3.78 (s, 3H), 3.97 (d, J=5.1 Hz, 2H), 5.20 (s, 1H), 6.82(d, J=8.4 Hz, 2H), 7.09 (d, J=8.4 Hz, 2H).

The compounds in the remainder of this example were synthesizedaccording to the procedure for III-30 described above using theappropriate Grignard reagent.

tert-butyl 3-(4-methoxyphenyl)-2-oxopropylcarbamate (III-1): ¹H NMR(CDCl₃, 300 MHz) δ 1.43 (s, 9H), 3.66 (s, 2H), 3.80 (s, 3H), 3.95 (d,J=5.1 Hz, 2H), 6.48 (br s, 1H), 6.87 (d, J=8.4 Hz, 2H), 7.13 (d, J=8.4Hz, 2H).

tert-butyl 3-(4-ethoxyphenyl)-2-oxopropylcarbamate (III-2): mp 58-59° C.¹H NMR (CDCl₃, 300 MHz) δ 1.41 (t, J=6.6 Hz, 3H), 1.43 (s, 9H), 3.65 (s,2H), 4.01 (q, J=6.6 Hz, 2H), 4.05 (s, 2H), 5.18 (br s, 1H), 6.85 (d,J=8.4 Hz, 2H), 7.11 (d, J=8.4 Hz, 2H).

tert-butyl 3-(3,4-dimethoxyphenyl)-2-oxopropylcarbamate (III-3): ¹H NMR(CDCl₃, 300 MHz) δ 1.43 (s, 9H), 3.66 (s, 2H), 3.87 (s, 6H), 4.07 (br s,2H), 5.18 (br s, 1H), 6.70-6.86 (m, 3H).

tert-butyl 3-(3,5-dimethoxyphenyl)-2-oxopropylcarbamate (III-4): (0.51g, 18%). ¹H NMR (CDCl₃, 300 MHz) δ 1.43 (s, 9H), 3.65 (s, 2H), 3.78 (s,6H), 4.06 (br s, 2H), 6.34-6.41 (m, 3H).

tert-butyl 3-(4-isopropoxyphenyl)-2-oxopropylcarbamate (III-5): (8.2 g,90 %). ¹H NMR (CDCl₃, 300 MHz) δ 1.33 (d, J=6 Hz, 6H), 1.43 (s, 9H),3.42 (br s, 2H), 4.04 (d, J=4.2 Hz, 2H), 4.52 (quintet, J=6.0 Hz, 1H),5.19 (br s, 1H), 6.84 (d, J=8.4 Hz, 2H), 7.10 (d, J=8.4 Hz, 2H).

tert-butyl 3-(4-methylthiophenyl)-2-oxopropylcarbamate (III-6): (1.99 g,73%): ¹H NMR (CDCl₃, 300 MHz) δ 1.43 (s, 9H), 2.48 (s, 3H), 3.68 (s,2H), 4.05 (d, J=4.2 Hz, 2H), 5.30 (br s, 1H), 7.13 (d, J=8.4 Hz, 2H),7.22 (d, J=8.4 Hz, 2H).

tert-butyl 3-(4-methylphenyl)-2-oxopropylcarbamate (III-8): (3.0 g,60%). Mp 64-65° C. ¹H NMR (CDCl₃, 300 MHz) δ 1.43 (s, 9H), 2.33 (s, 3H),3.68 (s, 2H), 4.04 (br s, 2H), 7.01-7.22 (m, 4H).

tert-butyl 3-(3-methylphenyl)-2-oxopropylcarbamate (III-9): (2.17 g,68%). ¹H NMR (CDCl₃, 300 MHz) δ 1.43 (s, 9H), 3.69 (s, 2H), 3.80 (s,3H), 3.82 (s, 2H), 6.70-6.91 (m, 3H), 7.19-7.32 (m, 1H).

tert-butyl 3-(4-isopropylphenyl)-2-oxopropylcarbamate (III-10): (7.45 g,86%): ¹H NMR (CDCl₃, 300 MHz) δ 1.24 (d, J=6.9 Hz, 6H), 1.43 (s, 9H),2.89 (quintet, J=6.9 Hz, 1H), 3.69 (s, 2H), 4.06 (d, J=4.8 Hz, 2H), 5.20(br s, 1H), 7.13 (d, J=8.4 Hz, 2H), 7.20 (d, J=8.4 Hz, 2H).

tert-butyl 3-(4-chlorophenyl)-2-oxopropylcarbamate (III-11): (1.83 g,43%): ¹H NMR (CDCl₃, 300 MHz) δ 1.43 (s, 9H), 3.70 (s, 2H), 4.06 (d,J=4.8 Hz, 2H), 5.18 (br s, 1H), 7.14 (d, J=7.8 Hz, 2H), 7.31 (d, J=7.8Hz, 2H).

tert-butyl 3-(3-chlorophenyl)-2-oxopropylcarbamate (III-12): (2.45 g,94%). ¹H NMR (CDCl₃, 300 MHz) δ 1.44 (s, 9H), 3.71 (s, 2H), 4.08 (br s,2H), 7.06-7.31 (m, 4H).

tert-butyl 3-(4-tert-butylphenyl)-2-oxopropylcarbamate (III-13): (1.0 g,34%): ¹H NMR (CDCl₃, 300 MHz) δ 1.31 (s, 9H), 1.32 (s, 9H), 3.68 (s,2H), 4.05 (d, J=4.2 Hz, 2H), 5.21 (br s, 1H), 7.13 (d, J=8.4 Hz, 2H),7.32 (d, J=8.4 Hz, 2H).

tert-butyl 3-(4-phenylphenyl)-2-oxopropylcarbamate (III-14): (3.45 g,71%). ¹H NMR (CDCl₃, 300 MHz) δ 1.43 (s, 9H), 3.77 (s, 2H), 4.11 (s,2H), 7.25-7.64 (m, 9H).

tert-butyl 3-(4-fluorophenyl)-2-oxopropylcarbamate (III-15): (2.24 g,56%). Mp: 80-81° C. ¹H NMR (CDCl₃, 300 MHz) δ 1.43 (s, 9H), 3.70 (s,2H), 4.06 (br s, 2H), 7.02 (t, J=8.4 Hz, 2H), 7.18 (q, J=8.7, 6.6 Hz,2H).

tert-butyl 3-(3-fluorophenyl)-2-oxopropylcarbamate (III-16): (0.6 g,24%): ¹H NMR (CDCl₃, 300 MHz) δ 1.44 (s, 9H), 3.73 (s, 2H), 4.07 (d,J=4.8 Hz, 2H), 5.18 (br s, 1H), 6.90-7.16 (m, 3H), 7.28-7.36 (m, 1H).

tert-butyl 3-(3-methoxyphenyl)-2-oxopropylcarbamate (III-18): (2.18 g,68%): ¹H NMR (CDCl₃, 300 MHz) δ 1.43 (s, 9H), 3.69 (s, 2H), 3.80 (s,3H), 4.06 (d, J=4.8 Hz, 2H), 5.18 (br s, 1H), 6.73-6.90 (m, 3H),7.21-7.30 (m, 1H).

tert-butyl 3-(3-fluoro-4-methylphenyl)-2-oxopropylcarbamate (III-19):(1.94 g, 55%). ¹H NMR (CDCl₃, 300 MHz) δ 1.43 (s, 9H), 2.27 (s, 3H),3.68 (s, 2H), 4.02 (br s, 2H), 6.81-7.20 (m, 3H).

tert-butyl 3-(3-fluoro-4-methoxyphenyl)-2-oxopropylcarbamate (III-20):(1.22 g, 39%). ¹H NMR (CDCl₃, 300 MHz) δ 1.43 (s, 9H), 3.65 (s, 2H),3.81 (s, 3H), 3.84 (s, 2H), 6.91-7.15 (m, 3H)

tert-butyl 3-(4-fluoro-3-methylphenyl)-2-oxopropylcarbamate(III-21):(1.5 g, 56%). ¹H NMR (CDCl₃, 300 MHz) δ 1.43 (s, 9H), 2.26 (s,3H), 3.65 (s, 2H), 4.05 (br s, 2H), 6.90-7.14 (m, 3H).

tert-butyl 3-(3-chloro-4-fluorophenyl)-2-oxopropylcarbamate (III-22):(2.51 g, 47%). ¹H NMR (CDCl₃, 300 MHz) δ 1.44 (s, 9H), 3.69 (s, 2H),4.07 (br s, 2H), 7.04-7.18 (m, 2H), 7.24-7.28 (m, 1H).

tert-butyl 3-(2,5-difluorophenyl)-2-oxopropylcarbamate (III-23): (2.7 g,53%). Mp: 73-74° C. ¹H NMR (CDCl₃, 300 MHz) δ 1.43 (s, 9H), 3.75 (s,2H), 4.09 (br s, 2H), 6.86-7.11 (m, 3H).

tert-butyl 3-(3-chloro-5-fluorophenyl)-2-oxopropylcarbamate (III-24):(2.56 g, 93%). ¹H NMR (CDCl₃, 300 MHz) δ 1.44 (s, 9H), 3.71 (s, 2H),4.08 (s, 2H), 6.81-6.89 (m, 1H), 6.97-7.07 (m, 2H).

tert-butyl 3-(2,4-difluorophenyl)-2-oxopropylcarbamate (III-25): (1.57g, 37%). ¹H NMR (CDCl₃, 300 MHz) δ 1.46 9s, 9H0, 3.73 (s, 2H), 4.09 (brs, 2H), 6.69-6.96 (m, 2H), 7.09-7.24 (m, 1H).

tert-butyl 3-(3,5-dichlorophenyl)-2-oxopropylcarbamate (III-26): (2.64g, 90%). ¹H NMR (CDCl₃, 300 MHz) δ 1.43 (s, 9H), 3.65 (s, 2H), 4.06 (brs, 2H), 6.34-6.41 (m, 3H).

tert-butyl 3-(3,4-difluorophenyl)-2-oxopropylcarbamate (III-27): (2.13g, 50%). Mp: 50-51° C. ¹H NMR (CDCl₃, 300 MHz) δ 1.43 (s, 9H), 3.69 (s,2H), 4.06 (br s, 2H), 6.85-7.23 (m, 3H).

tert-butyl 4-(4-fluorophenyl)-2-oxobutylcarbamate (III-28): (2.29 g,71%). ¹H NMR (CDCl₃, 300 MHz) δ 1.44 (s, 9H), 2.73 (t, J=7.2 Hz, 2H),2.91 (t, J=7.2 Hz, 2H), 3.97 (d, J=5.4 Hz, 2H), 6.96 (t, J=8.4 Hz, 2H),7.10-7.18 (m, 2H).

tert-butyl 4-(4-chlorophenyl)-2-oxobutylcarbamate (III-29): (2.05 g,55%). ¹H NMR (CDCl₃, 300 MHz) δ 1.44 (s, 9H), 2.74 (t, J=7.2 Hz, 2H),2.90 (t, J=7.2 Hz, 2H), 3.97 (d, J=2.7 Hz, 2H), 7.10 (d, J=8.9 Hz, 2H),7.25 (d, J=8.9 Hz, 2H).

tert-butyl 4-(4-ethoxyphenyl)-2-oxobutylcarbamate (III-31): (3.79 g,57%). ¹H NMR (CDCl₃, 300 MHz) δ 1.40 (t, J=8.4 Hz, 3H), 1.44 (s, 9H),2.71 (t, J=7.2 Hz, 2H), 2.89 (t, J=7.2 Hz, 2H), 3.96 (d, J=4.8 Hz, 2H),4.00 (q, J=6.6 Hz, 2H), 6.81 (d, J=8.7 Hz, 2H), 7.07 (d, J=8.7 Hz, 2H).

tert-butyl 4-(4-trifluoromethylphenyl)-2-oxobutylcarbamate (III-32):(0.97 g, 20%). ¹H NMR (CDCl₃, 300 MHz) δ 1.44 (s, 9H), 2.78 (t, J=7.2Hz, 2H), 3.00 (t, J=7.2 Hz, 2H), 3.99 (d, J=4.8 Hz, 2H), 7.29 (d, J=8.1Hz, 2H), 7.54 (d, J=8.1 Hz, 2H).

tert-butyl 4-(4-n-butoxyphenyl)-2-oxobutylcarbamate (III-33): (1.24 g,13%). ¹H NMR (CDCl₃, 300 MHz) δ 0.97 (t, J=7.2 Hz, 3H), 1.44 (s, 9H),1.46-1.54 (m, 2H) 1.69-1.81 (m, 2H), 2.72 (t, J=7.8 Hz, 2H), 2.87 (t,J=7.8 Hz, 2H), 3.87-7.01 (m, 4H), 6.81 (d, J=8.7 Hz, 2H), 7.07 (d, J=8.7Hz, 2H).

tert-butyl 4-(3-methylphenyl)-2-oxobutylcarbamate (III-34): (6.13 g,97%). ¹H NMR (CDCl₃, 300 MHz) δ 1.44 (s, 9H), 2.32 (s, 3H), 2.74 (t,J=7.2 Hz, 2H), 2.90 (t, J=7.2 Hz, 2H), 3.98 (d, J=4.8 Hz, 2H), 6.90-7.06(m, 3H), 7.17 (t, J=8.1 Hz, 1H).

tert-butyl 4-(3-methoxyphenyl)-2-oxobutylcarbamate (III-35): (6.63 g,99%). ¹H NMR (CDCl₃, 300 MHz) δ 1.44 (s, 9H), 2.76 (t, J=7.2 Hz, 2H),2.90 (t, J=7.2 Hz, 2H), 3.79 (s, 3H), 3.98 (d, J=4.8 Hz, 2H), 6.68-6.84(m, 3H), 7.20 (t, J=7.8 Hz, 1H).

tert-butyl 4-(4-methylphenyl)-2-oxobutylcarbamate (III-36): (3.04 g,80%). Mp: 62-63° C. ¹H NMR (CDCl₃, 300 MHz) δ 1.44 (s, 9H), 2.31 (s,3H), 2.73 (t, J=7.2 Hz, 2H), 2.90 (t, J=7.2 Hz, 2H), 3.97 (d, J=4.2 Hz,2H), 7.02-7.14 (m, 4H).

tert-butyl 4-(3-fluoro-5-trifluoromethylphenyl)-2-oxobutylcarbamate(III-37): (0.19 g, 33%). ¹H NMR (CDCl₃, 300 MHz) δ 1.44 (s, 9H), 2.79(t, J=7.2 Hz, 2H), 3.00 (t, J=7.2 Hz, 2H), 3.99 (d, J=4.8 Hz, 2H),7.06-7.31 (m, 3H).

Example 2 Alternate Synthesis of Compounds of Formula III

3-(3-Trifluoromethylphenyl)-2-oxopropyl bromide: To a cooled solution of3-trifluoromethylphenyl acetic acid (1.0 g, 4.9 mmol) in dichloromethane(15 mL) was added dropwise oxalyl chloride (0.73 mL, 8.2 mmol, 1.7 eq).The mixture was stirred at 5° C. for 5 min, then DMF (10 drops) wasadded. The resulting mixture was stirred at ice-cooled bath for 30 min,then concentrated in vacuo. The residue was used directly in the nextstep without further purification. It was dissolved in dichloromethane(15 mL). The mixture was cooled in an ice-bath. To this cooled solutionwas added dropwise a solution of trimethylsilyldiazomethane in hexane(2.0 M, 2.5 mL, 5.0 mmol). The resulting mixture was stirred in an icebath for 45 min, concentrated in vacuo. The residue was used directly inthe nest step without any further purification. To a cooled solution ofproduct from previous step in dichloromethane (15 mL) was added 30% HBrin HOAc (0.61 mL). The resulting mixture was heated at 55° C. for 45min, cooled to room temperature. Saturated NaHCO₃ solution (˜5 mL) wasadded. The organic layer was separated, washed with H₂O (20 mL) andbrine (20 mL), dried (MgSO₄), filtered, and concentrated to give abrownish oil. MS: 281 (M+H)⁺.

3-(3-Trifluoromethylphenyl)-2-oxopropylazide: The oil was dissolved inDMF (10 mL). The solution was cooled in an ice bath, and NaN₃ (0.64 g,9.8 mmol) was added. The resulting reaction mixture was stirred at 5° C.for 2 hours, then poured. into H₂O (30 mL). The mixture was extractedwith EtOAc (2×20 mL). The combined organic layers were washed with brine(20 mL), dried (MgSO4), filtered, and concentrated. The residue waspurified on flash column chromatography (silica gel, 5-10% EtOAc/hexane)to give a yellow oil (0.23 g, 19%). ¹H NMR (CDCl₃, 300 MHz) δ 3.82 (s,2H), 4.02 (s, 2H), 7.36-7.59 (m, 4H). MS: 244 (M+H)⁺.

3-(3-Trifluoromethylphenyl)-2-oxopropylamine hydrochloride: A mixture ofazide (0.47 g, 193 mmol), 12N HCl (0.5 mL), and 10% Pd/C (50% wet, 0.47g) in MeOH (30 mL) was hydrogenated at 5 psi for 2 hours. The mixturewas filtered through a pad of Celite. The filtrate was concentrated invacuo to give a light brow semisolid (0.49 g). MS: 218 (M+H)⁺.

N-t-Butoxycarbonyl-3-(3-trifluoromethylphenyl)-2-oxopropylamine(III-17): To a stirred suspension of amine hydrochloride (0.49 g) indichloromethane (10 mL) was added successively a solution of NaHCO₃(0.16 g) in H₂O (3 mL), NaCl (0.39 g), and a solution of Boc₂O (0.422 g)in dichloromethane (5 mL). The resulting mixture was heated to refluxfor 90 min, cooled to room temperature, and diluted with H₂O (10 mL),and extracted with dichloromethane (2×10 mL), dried (MgSO4), filtered,and concentrated. The residue was purified on flash columnchromatography (silica gel, 10 EtOAc/hexane) to give an oil (0.54 g). ¹HNMR (CDCl₃, 300 MHz) δ 1.44 (s, 9H), 3.80 (s, 2H), 4.08 (br s, 2H),7.36-7.58 (m, 4H).

3-(3-Methylthiophenyl)-2-oxopropyl bromide: To a cooled solution of3-methylthiophenylacetic acid (4.2 g, 23 mmol) in dichloromethane (68mL) was added dropwise oxalyl chloride (3.48 mL, 39.2 mmol, 1.7 eq). Themixture was stirred at 5° C. for 5 min, then DMF (335 μL) was added. Theresulting mixture was stirred at ice-cooled bath for 30 min, thenconcentrated in vacuo. The residue was used directly in the next stepwithout further purification. It was dissolved in dichloromethane (68mL). The mixture was cooled in an ice-bath. To this cooled solution wasadded dropwise a solution of trimethylsilyldiazomethane in hexane (2.0M, 12.1 mL, 24.2 mmol). The resulting mixture was stirred in an ice bathfor 45 min, concentrated in vacuo. The residue was used directly in thenest step without any further purification. To a cooled solution ofproduct from previous step in dichloromethane (70 mL) was added 45% HBrin HOAc (3.1 mL). The resulting mixture was heated at 55° C. for 45 min,cooled to room temperature. Saturated NaHCO₃ solution (23 mL) was added.The organic layer was separated, washed with H₂O (20 mL) and brine (20mL), dried (MgSO₄), filtered, and concentrated to give a brownish oil(5.02 g). MS: 275 (M+H)⁺.

3-(3-Methylthiophenyl)-2-oxopropylazide: The oil was dissolved in DMF(46 mL). The solution was cooled in an ice bath, and NaN₃ (2.99 g, 46mmol) was added. The resulting reaction mixture was stirred at 5° C. for2 hours, then poured, into H₂O (30 mL). The mixture was extracted withEtOAc (2×20 mL). The combined organic layers were washed with brine (20mL), dried (MgSO4), filtered, and concentrated. The residue was purifiedon flash column chromatography (silica gel, 5-10% EtOAc/hexane) to givea yellow oil (0.78 g, 50%). ¹H NMR (CDCl₃, 300 MHz) δ 2.48 (s, 3H), 3.71(s, 2H), 3.99 (s, 2H), 6.98 (d, J=7.2 Hz, 1H), 7.09 (br s, 1H), 7.18(dt, J=8.7, 2.1 Hz, 1H), 7.25-7.31 (m, 1H) MS: 222 (M+H)⁺.

3-(3-Methylthiophenyl)-2-oxopropylamine hydrochloride: To a solution of3-(3-Methyltiophenyl)-2-oxopropylazide (2.26 g, 10.3 mmol) in EtOH (82mL) was added SnCl₂ (5.84 g, 30.8 mmol). The resulting mixture wasrefluxed under N2 for 30 min, and then concentrated in vacuo. Theresidue was purified on flash column chromatography (silica gel, 10-12%MeOH/CH₂Cl₂ with 0.1 % NH₄OH) to give a semisolid (2.01 g, 100%). ¹H NMR(CDCl₃, 300 MHz) δ 2.47 (s, 3H), 3.86 (s, 2H), 4.03 (s, 2H), 7.03 (d,J=7.2 Hz, 1H), 7.17 (s, 1H), 7.19-7.22 (m, 1H), 7.24-7.31 (m, 1H). MS:196 (M+H)⁺.

N-t-Butoxycarbonyl-3-(3-methylthiophenyl)-2-oxopropylamine (III-7): To astirred suspension of amine hydrochloride (0.443 g) in dichloromethane(10 mL) was added successively a solution of NaHCO₃ (0.16 g) in H₂O (3mL), NaCl (0.39 g), and a solution of Boc₂O (0.422 g) in dichloromethane(5 mL). The resulting mixture was heated to reflux for 90 min, cooled toroom temperature, and diluted with H₂O (10 mL), and extracted withdichloromethane (2×10 mL), dried (MgSO4), filtered, and concentrated.The residue was purified on flash column chromatography (silica gel, 10EtOAc/hexane) to give an oil (0.17 g, 25%). ¹H NMR (CDCl₃, 300 MHz) δ1.44 (s, 9H), 2.48 (s, 3H), 3.69 (s, 2H), 4.06 (br s, 2H), 6.98 (d,J=7.2 Hz, 1H), 7.09 (br s, 1H), 7.13-7.20 (m, 1H), 7.24-7.31 (m, 1H).

Example 3 Synthesis of ω-phenyl Alkyl Bromides

3-Fluoro-5-trifluoromethylphenyl ethanol: To cooled solution of methyl3-fluoro-5-trifluoromethylphenyl acetate (6.54 g, 27.7 mmol) in hexane(30 mL) was added a solution of DIBAL in toluene (1.5 M, 40 mL, 60mmol). The cooling bath was removed. The reaction mixture was stirred atroom temperature for 90 min. The reaction mixture was cooled in an icebath, and MeOH (55 mL) was added, followed by aqueous HCl (6 N, 11 mL).The resulting mixture was extracted with ether (2×30 mL). The combinedether layers were washed with brine (20 mL), dried (Na₂SO₄), filtered,and concentrated to give the product (5.7 g, 100%). 1H NMR (CDCl₃, 300MHz) d 2.93 (t, J=6.4 Hz, 2H), 3.91 (t, J=6.4 Hz, 2H),7.12-7.35 (m, 3H).

3-Fluoro-5-trifluoromethylphenylethylbromide: To a stirred solution of3-fluoro-5-trifluoromethylphenyl ethanol (2.82 g, 13.5 mmol) indichloromethane (90 mL) was added PPh₃ (4.26 g, 16.2 mmol), followed byCBr₄ (6.74 g, 20.3 mmol). The reaction mixture was stirred at roomtemperature under N₂ and monitored by TLC. After stirring at roomtemperature for 3 hours, TLC showed that the reaction was completed. Thereaction mixture was poured into a solution of saturated NaHCO₃ (30 mL).The layers were separated. The aqueous layer was extracted withdichloromethane (2×30 mL). The combined organic layers were washed withbrine (30 mL), dried (Na₂SO₄), filtered, and concentrated in vacuo. Theresidue was purified on flash column chromatography (silica gel, 2%EtOAc/hexane) to the product (2.28 g, 62%). ¹H NMR (CDCl₃, 300 MHz) δ3.23 (t, J=7.2 Hz, 2H), 3.59 (t, J=7.2 Hz, 2H), 7.10-7.35 (m, 3H).

Methyl 4-Trifluoromethylphenyl acetate: (5.97 g, 100%). ¹H NMR (CDCl₃,300 MHz) δ 3.70 (s, 2H), 3.71 (s, 3H), 7.41 (d, J=8.1 Hz, 2H), 7.59 (d,J=8.1 Hz, 2H).

4-Trifluoromethylphenyl ethanol: To a cooled solution of LAH in THF (1M, 28 mL, 28 mmol) was added dropwise a solution of methyl4-trifluoromethylphneyl acetate (5.97 g, 27 mmol) in THF (10 mL). Theresulting mixture was stirred at room temperature for 2 hours, and thencooled in an ice bath. To this cooled mixture was added a saturatedsolution of NH₄Cl (excess). The resulting mixture was filtered. Thesolid was washed with EtOAc. The combined filtrate was washed with brine(20 mL), dried (MgSO₄), filtered, and concentrated in vacuo to give aoil (4.46 g, 87%). ¹H NMR (CDCl₃, 300 MHz) δ 2.94 (t, J=7.2 Hz, 2H),3.90 (t, J=7.2 Hz, 2H), 7.36 (d, J=8.1 Hz, 2H), 7.58 (d, J=8.1 Hz, 2H).

Example 4 Synthesis of Fluoro-substituted Boc-protected Precursors ofFormula I (E)- and(Z)-N-t-Butoxycarbonyl-3-fluoro-2-{2-(4-methoxyphenyl)ethyl}allylamine

To a cooled suspension of fluoromethyltriphenylphosphoniumtetrafluoroborate (ref: J. Fluorine Chem., 1985, 27, 85-89) (1.76 g,4.61 mmol, 2 eq) in THF at 0° C. was added NaH (0.114 g, 4.75 mmol, 2.06eq). The resulting mixture was stirred at 0° C. for one hour, at whichtime a solution ofN-t-Butoxycarbonyl-4-(4-methoxyphenyl)-2-oxobutylamine (0.677 g, 2.31mmol, 1 eq) in THF (10 mL) was added slowly. Upon completion of theaddition, the ice-bath was then removed and the reaction was allowed tostir at room temperature overnight. The reaction mixture was poured intoa beaker containing ice water (80 mL). The aqueous layer was extractedwith ethyl acetate (2×70 mL), and the combined organic layers werewashed with brine, dried (Na₂SO₄), filtered, and concentrated in vacuoto give an oil. It was then purified on flash column chromatography(silica gel, 2% EtOAc/hexane) to give the (E)-isomer as a white solid(0.244 g, 34%) m.p.: 40-41° C., ¹H NMR (CDCl₃, 300 MHz) δ 1.45 (s, 9H),2.38 (t, J=8.1 Hz, 2H), 2.71 (t, J=6.6 Hz, 2H), 3.60 (s, 2H), 4.40 (s,1H), 6.52 (d, J=84 Hz, 1H), 6.83 (d, J=8.4 Hz, 2H), 7.13 (d, J=8.4 Hz,1H). (Z)-isomer as a white solid (0.181 g, 25%). m.p.: 32-33° C. ¹H NMR(CDCl₃, 300 MHz) δ 1.46 (s, 9H), 2.20 (m, 2H), 2.68 (t, J=8.1 Hz, 2H),3.85 (s, 3H), 3.91 (d, J=5.1 Hz, 1H), 4.52 (s, 1H), 6.36 (d, J=85 Hz,1H), 6.82 (d, J=8.4 Hz, 2H), 7.07 (d, J=8.4 Hz, 2H). The compounds inthe remainder of this example were synthesized according to theprocedure for (E)- and(Z)-N-t-Butoxycarbonyl-3-fluoro-2-{2-(4-methoxyphenyl)ethyl}allylaminedescribed above using the appropriate starting material synthesized fromExamples 1 or 2.

((E)- and (Z)-N-t-Butoxycarbonyl-3-fluoro-2-(4-methoxybenzyl)allylamine:(E)-isomer: 52-53° C. ¹HNMR (CDCl₃, 300 MHz) δ 1.43 (s, 9H), 3.39 (s,2H), 3.54 (br s, 2H), 3.79 (s, 3H), 4.38 (br s, 1H), 6.64 (d, J=84.3 Hz,1H), 6.83 (d, J=8.4 Hz, 2H), 7.14 (d, J=8.4 Hz, 2H). (Z)-isomer: 37-38°C. ¹HNMR (CDCl₃, 300 MHz) δ 1.44 (s, 9H), 3.18 (s, 2H), 3.79 (br s, 5H),4.50 (br s, 1H), 6.45 (d, J=84.3 Hz, 1H), 6.84 (d, J=8.4 Hz, 2H), 7.11(d, J=8.4 Hz, 2H).

(E)- and (Z)-N-t-Butoxycarbonyl-3-fluoro-2-(4-ethoxybenzyl)allylamine:(E)-isomer: mp 48-49° C. ¹HNMR (CDCl₃, 300 MHz) δ 1.40 (t, J=6.6 Hz,3H), 1.43 (s, 9H), 3.39 (br s, 2H), 3.53 (br s, 2H), 4.00 (q, J=6.6 Hz,2H), 4.39 (br s, 1H), 6.63 (d, J=84.9 Hz, 1H), 6.82 (d, J=8.4 Hz, 2H),7.12 (d, J=8.4 Hz, 2H). (Z)-isomer: ¹HNMR (CDCl₃, 300 MHz) δ 1.40 (t,J=6.6 Hz, 3H), 1.44 (s, 9H), 3.18 (br s, 2H), 3.78 (br s, 2H), 4.01 (q,J=6.6 Hz, 2H), 4.50 (br s, 1H), 6.44 (d, J=84.9 Hz, 1H), 6.82 (d, J=8.4Hz, 2H), 7.10 (d, J=8.4 Hz, 2H).

(E)- and(Z)-N-t-Butoxycarbonyl-3-fluoro-2-(3,4-dimethoxybenzyl)allylamine:(E)-isomer: ¹HNMR (CDCl₃, 300 MHz) δ 1.43 (s, 9H), 3.39 (s, 2H), 3.56(br s, 2H), 3.85 (s, 3H), 3.87 (s, 3H), 4.45 (br s, 1H), 6.64 (d, J=84.3Hz, 1H), 6.71-6.82 (m, 3H). (Z)-isomer: ¹HNMR (CDCl₃, 300 MHz) δ 1.44(s, 9H), 3.19 (s, 2H), 3.80 (s, 2H), 3.86 (s, 3H), 3.88 (s, 3H), 4.50(br s, 1H), 6.47 (d, J=84.6 Hz, 1H), 6.68-6.90 (m, 3H).

(E)-N-t-Butoxycarbonyl-3-fluoro-2-(4-isopropoxybenzyl)allylamine: ¹H NMR(CDCl₃, 300 MHz) δ 1.32 (d, J=6.0 Hz, 6H), 1.43 (s, 9H), 3.38 (s, 2H),3.54 (br s, 2H), 4.39 (br s, 1H), 4.50 (quintet, J=6.0 Hz, 1H), 6.64 (d,J=84.9 Hz, 1H), 6.81 (d, J=8.7 Hz, 2H), 7.11 (d, J=8.7 Hz, 2H).

(E)-N-t-Butoxycarbonyl-3-fluoro-2-(4-isopropylbenzyl)allylamine: (0.3 g,16%): ¹H NMR (CDCl₃, 300 MHz) δ 1.23 (d, J=6.6 Hz, 6H), 1.42 (s, 9H),2.87 (quintet, J=6.6 Hz, 1H), 3.42 (s, 2H), 3.54 (br s, 2H), 4.43 (br s,1H), 6.64 (d, J=84.3 Hz, 1H), 6.95 (d, J=6.6 Hz, 2H), 7.33 (d, J=6.6 Hz,2H).

(E)-N-t-Butoxycarbonyl-3-fluoro-2-(3-fluoro-5-trifluoromethylphenylethyl)-allylamine:(0.29 g, 41%). Mp: 60-61° C. ¹H NMR (CDCl₃, 300 MHz) δ 1.46 (s, 9H),2.33-2.52 (m, 2H), 2.76-2.91 (m, 2H), 3.66 (br s, 2H), 6.53 (d, J=83.7Hz, 1H), 7.09-7.23-7.09 (m, 2H), 7.26-7.30 (m, 1H).

(Z)-N-t-Butoxycarbonyl-3-fluoro-2-(3-fluorophenylethyl)allylamine: (0.08g, 21%). Mp: 67-68° C. ¹H NMR (CDCl₃, 300 MHz) δ 1.46 (s, 9H), 2.17-2.28(m, 2H), 2.70-2.81 (m, 2H), 3.92 (br s, 2H), 6.36 (d, J=83.7 Hz, 1H),6.83-6.99 (m, 3H), 7.17-7.31 (m, 1H).

(E)-N-t-Butoxycarbonyl-3-fluoro-2-(3-fluorophenylethyl)allylamine: (0.15g, 41%). ¹HNMR (CDCl₃, 300 MHz) δ 1.45 (s, 9H), 2.33-2.47 (m, 2H),2.68-2.82 (m, 2H), 3.62 (br s, 2H), 6.52 (d, J=83.7 Hz, 1H), 6.78-7.03(m, 3H), 7.12-7.31 (m, 1H).

Example 5 Alternate Synthesis of Fluoro-substituted Boc-protectedPrecursors of Formula I(Z)-N-t-Butoxycarbonyl-3-fluoro-2-(4-isopropoxybenzyl)allylamine

To a suspension of FCH₂P⁺Ph₃BF₄ ⁻ (4.98 g, 13.02 mmol) in THF (80 mL) at−78° C. under nitrogen was added a solution of sodium bis(trimethysilyl)amide (NaHMDS) in THF (1.0M, 13.67 mL, 13.67 mmol). The reaction mixturewas stirred at −78° C. under nitrogen for 1 h and then a solution ofN-t-butoxycarbonyl-3-(4-isopropoxyphenyl)-2-oxopropylamine (2.00 g, 6.51mmol) in THF (60 mL) was slowly added. The resulting mixture was stirredat −78° C. for 4.5 h and then allowed to warm gradually to roomtemperature. The mixture was stirred at room temperature overnight andthen poured into cold water (50 mL). The layers were separated. Theaqueous layer was extracted with EtOAc (3×50 mL). The combined organiclayers were dried (Na₂SO₄), filtered, and concentrated in vacuo. Theresidue was purified on flash column chromatography (silica gel, 0-5%EtOAc/Hexane) to give the desired product as a colorless oil (0.95 g,45%). ¹H NMR (CDCl₃, 300 MHz) δ 1.32 (d, J=6.0 Hz, 6H), 1.43 (s, 9H),3.17 (d, J=3.9 Hz, 2H), 3.79 (br s, 2H), 4.51 (quintet, J=6.0 Hz, 1H),6.45 (d, J=84.3 Hz, 1H), 6.82 (d, J=8.7 Hz, 2H), 7.09 (d, J=8.4 Hz, 2H).

The compounds in the remainder of this example were synthesizedaccording to the procedure for(Z)-N-t-Butoxycarbonyl-3-fluoro-2-(4-isopropoxybenzyl)allylaminedescribed above using the appropriate starting material synthesized fromExamples 1 or 2.

(Z)-N-t-Butoxycarbonyl-3-fluoro-2-(4-isopropylbenzyl) allylamine: (1.05g, 66%): ¹H NMR (CDCl₃, 300 MHz) δ 1.23 (d, J=6.9 Hz, 6H), 1.43 (s, 9H),2.88 (quintet, J=6.9 Hz, 1H), 3.21 (d, J=3.0 Hz, 2H), 3.79 (br s, 2H),4.48 (br s, 1H), 6.46 (d, J=84.9 Hz, 1H), 7.11 (d, J=8.9 Hz, 2H), 7.16(d, J=8.9 Hz, 2H).

(Z)-N-t-Butoxycarbonyl-2-(4-chlorolbenzyl)-3-fluoroallylamine: (0.32 g,33%): ¹H NMR (CDCl₃, 300 MHz) δ 1.43 (s, 9H), 3.21 (d, J=3.0 Hz, 2H),3.78 (br s, 2H), 4.50 (br s, 1H), 6.46 (d, J=84.3 Hz, 1H), 7.14 (d,J=7.8 Hz, 2H), 7.26 (d, J=7.8 Hz, 2H).

(Z)-N-t-Butoxycarbonyl-3-fluoro-2-(4-methylthiobenzyl)allylamine: (0.56g, 56%): ¹H NMR (CDCl₃, 300 MHz) δ 1.43 (s, 9H), 2.47 (s, 3H), 3.20 (d,J=3.6 Hz, 2H), 3.79 (br s, 2H), 4.49 (br s, 1H), 6.46 (d, J=84.3 Hz,1H), 7.13 (d, J=7.8 Hz, 2H), 7.24 (d, J=7.8 Hz, 2H).

(Z)-N-t-Butoxycarbonyl-2-(4-tert-butylbenzyl)-3-fluoroallylamine: (0.25g, 25%): ¹H NMR (CDCl₃, 300 MHz) δ 1.31 (s, 9H), 1.43 (s, 9H), 3.21 (d,J=3.0 Hz, 2H), 7.32 (d, J=8.4 Hz, 2H).

(Z)-N-t-Butoxycarbonyl-3-fluoro-2-(3-fluorobenzyl)allylamine: (0.129 g,23%): ¹H NMR (CDCl₃, 300 MHz) δ 1.43 (s, 9H), 3.24 (d, J=3.3 Hz, 2H),3.79 (br s, 2H), 4.55 (br s, 1H), 6.48 (d, J=84.0 Hz, 1H), 6.84-7.06 (m,3H), 7.19-7.32 (m, 1H).

(Z)-N-t-Butoxycarbonyl-3-fluoro-2-(3-methoxybenzyl)allylamine: (0.18 g,17%): ¹H NMR (CDCl₃, 300 MHz) δ 1.45 (s, 9H), 3.23 (s, 2H), 3.76-3.85(m, 5H), 4.49 (br s, 1H), 6.48 (d, J=84.0 Hz, 1H), 6.71-6.88 (m, 3H),7.18-7.32 (m, 1H).

(Z)-N-t-Butoxycarbonyl-3-fluoro-2-(4-methylbenzyl)allylamine: (0.86 g,81%). Mp 68-69° C. ¹H NMR (CDCl₃, 300 MHz) δ 1.43 (s, 9H), 2.32 (s, 3H),3.21 (d, J=3.0 Hz, 2H), 3.78 (br s, 2H), 6.46 (d, J=84.9 Hz, 2H),7.05-7.15 (m, 4H).

(Z)-N-t-Butoxycarbonyl-3-fluoro-2-(4-phenylbenzyl)allylamine: (0.27 g,20%). Mp: 102-103° C. ¹H NMR (CDCl₃, 300 MHz) δ 1.44 (s, 9H), 3.29 (d,J=3.6 Hz, 2H), 3.82 (br s, 2H), 6.51 (d, J=84.3 Hz, 1H), 7.25-7.61 (m,9H).

(Z)-N-t-Butoxycarbonyl-3-fluoro-2-(3-fluoro-4-methylbenzyl)allylamine:(0.4 g, 42%). ¹H NMR (CDCl₃, 300 MHz) δ 1.43 (s, 9H), 2.24 (s, 3H), 3.21(d, J=3.6 Hz, 2H), 3.68 (s, 2H), 3.78 (br s, 2H), 6.47 (d, J=8.4 Hz,1H), 6.80-7.15 (m, 3H).

(Z)-N-t-Butoxycarbonyl-3-fluoro-2-(3-fluoro-4-methoxybenzyl)allylamine:(0.26 g, 30%). ¹H NMR (CDCl₃, 300 MHz) δ 1.43 (s, 9H), 3.18 (d, J=3.9Hz, 2H), 3.78 (br s, 2H), 3.89 (s, 3H), 6.47 (d, J=84 Hz, 1H), 6.84-6.99(m, 3H).

(Z)-N-t-Butoxycarbonyl-3-fluoro-2-(4-fluoro-3-methylbenzyl)allylamine:(0.39 g, 46%). ¹H NMR (CDCl₃, 300 MHz) δ 1.43 (s, 9H), 2.25 (s, 3H),3.18 (d, J=3.3 Hz, 2H), 3.77 (br s, 2H), 6.46 (d, J=84.3 Hz, 1H),6.87-7.05 (m, 3H).

(Z)-N-t-Butoxycarbonyl-3-fluoro-2-(3-chloro-4-fluorobenzyl)allylamine:(0.24g, 20%). ¹H NMR (CDCl₃, 300 MHz) δ 1.43 (s, 9H), 3.21 (d, J=3.0 Hz,2H), 3.77 (br s, 2H), 6.48 (d, J=83.4 Hz, 1H), 7.03-7.12 (m, 2H),7.19-7.28 (m, 1H).

(Z)-N-t-Butoxycarbonyl-3-fluoro-2-(2,5-difluorobenzyl)allylamine: (0.1g, 12%). Mp: 82-83° C. ¹H NMR (CDCl₃, 300 MHz) δ 1.41 (s, 9H), 3.24 (d,J=3.9 Hz, 2H), 3.79 (br s, 2H), 6.45 (d, J=84.3 Hz, 2H), 6.79-7.02 (m,3H).

(Z)-N-t-Butoxycarbonyl-3-fluoro-2-(3-chloro-5-fluorobenzyl)allylamine:(0.15 g, 25%). ¹H NMR (CDCl₃, 300 MHz) δ 1.43 (s, 9H), 3.22 (d, J=3.0Hz, 2H), 3.79 (br s, 2H), 6.50 (d, J=83.7 Hz, 2H), 6.80-7.04 (m, 3H).

(Z)-N-t-Butoxycarbonyl-3-fluoro-2-(2,4-difluorobenzyl)allylamine: (0.3g, 27%). ¹H NMR (CDCl₃, 300 MHz) δ 1.44 (s, 9H), 3.25 (d, J=3.0 Hz, 2H),3.81 (br s, 2H), 6.45 (d, J=84.3 Hz, 1H), 6.74-6.89 (m, 2H), 7.14-7.28(m, 1H).

(Z)-N-t-Butoxycarbonyl-3-fluoro-2-(3,5-dichlorobenzyl)allylamine: (0.17g, 16%). ¹H NMR (CDCl₃, 300 MHz) δ 1.43 (s, 9H), 3.12 (d, J=3.0 Hz, 2H),3.80 (br s, 2H), 6.51 (d, J=84.3 Hz, 1H), 7.10 (br s, 2H), 7.22-7.26 (m,1H).

(Z)-N-t-Butoxycarbonyl-3-fluoro-2-(3,4-difluorobenzyl)allylamine: (0.2g, 18%). ¹H NMR (CDCl₃, 300 MHz) δ 1.36 (s, 9H), 3.14 (d, J=3.0 Hz, 2H),3.71 (br s, 2H), 6.42 (d, J=83.4 Hz, 1H), 6.82-7.07 (m, 3H).

(Z)-N-t-Butoxycarbonyl-3-fluoro-2-(3-fluoro-5-trifluoromethylphenylethyl)-allylamine:(0.16 g, 26%). Mp: 62-63° C. ¹H NMR (CDCl₃, 300 MHz) δ 1.47 (s, 9H),2.16-2.29 (m, 2H), 2.76-2.90 (m, 2H), 3.95 (br s, 2H), 6.38 (d, J=83.7Hz, 1H), 7.05-7.34 (m, 3H).

(Z)-N-t-Butoxycarbonyl-3-fluoro-2-(3-methylbenzyl)allylamine: (1.35 g,23%). ¹H NMR (CDCl₃, 300 MHz) δ 1.44 (s, 9H), 2.33 (s, 3H), 3.21 (d,J=3.6 Hz, 2H), 3.79 (s, 2H), 6.46 (d, J=84.3 Hz, 1H), 6.95-7.10 (m, 3H),7.19-7.29 (m, 1H).

(Z)-N-t-Butoxycarbonyl-3-fluoro-2-(3-trifluoromethylbenzyl)allylamine:(0.13 g, 23%). ¹H NMR (CDCl₃, 300 MHz) δ 1.42 (s, 9H), 3.29 (br s, 2H),3.81 (br s, 2H), 6.46 (d, J=84.3 Hz, 2H), 6.79-7.56 (m, 4H).

(Z)-N-t-Butoxycarbonyl-3-fluoro-2-(3-methylthiobenzyl)allylamine: (0.2g, 45%). ¹H NMR (CDCl₃, 300 MHz) δ 1.44 (s, 9H), 2.48 (s, 3H), 3.22 (d,J=3.0 Hz, 2H), 3.79 (br s, 2H), 6.47 (d, J=84 Hz, 1H), 6.94-7.01 (m,1H), 7.07-7.15 (m, 2H), 7.18-7.26 (m, 1H).

(Z)-N-t-Butoxycarbonyl-3-fluoro-2-(4-fluorobenzyl)allylamine: (0.24 g,36%). ¹H NMR (CDCl₃, 300 MHz) δ 1.43 (s, 9H), 3.22 (d, J=3.6 Hz, 2H),3.77 (br s, 2H), 6.46 (d, J=84.3 Hz, 1H), 6.98 (t, J=8.7 Hz, 2H),7.11-7.22 (m, 2H).

(Z)-N-t-Butoxycarbonyl-3-fluoro-2-(3-chlorobenzyl)allylamine: (0.08 g,19%). ¹H NMR (CDCl₃, 300 MHz) δ 1.43 (s, 9H), 3.23 (d, J=3.0 Hz, 2H),3.79 (br s, 2H), 6.48 (d, J=83.4 Hz, 1H), 7.06-7.35 (m, 4H).

(Z)-N-t-Butoxycarbonyl-3-fluoro-2-(3,5-dimethoxybenzyl)allylamine: (0.12g, 20%). ¹H NMR (CDCl₃, 300 MHz) δ 1.43 (s, 9H), 3.18 (d, J=3.9 Hz, 2H),3.78 (br s, 8H), 6.30-6.40 (m, 3H), 6.48 (d, J=83.4 Hz, 1H).

Example 6 Synthesis of Chloro-substituted Boc-protected Precursors ofFormula I

General procedures for the preparation of (E) and(Z)-N-t-butoxycarbonyl-3-chloro-2-(arylethyl)allylamine: To a cooledsuspension of NaH (1.5 eq) in THF (30 mL) was added(chloromethyl)triphenylphosphonium chloride (1.1 eq). The resultingmixture was stirred at 0° C. for 1 hour, and then a solution of aN-t-butoxycarbonyl-4-substituted-2-oxobutylamine (1.0 eq, prepared fromExamples 1 or 2) was added during a period of 10-15 min. The resultingmixture was stirred at room temperature overnight, and then poured intocold water (40 mL). The layers were separated. The aqueous layer wasextracted with EtOAc (2×20 mL). The combined organic layers were washedwith brine (20 mL), dried (MgSO₄), filtered, and concentrated in vacuo.The residue was purified on flash column chromatography (silica gel,5-10% EtOAc/hexane) to E and Z isomers.

(E)-N-t-Butoxycarbonyl-3-chloro-2-(4-fluorophenylethyl)allylamine: (0.42g, 67%). ¹H NMR (CDCl₃, 300 MHz) δ 1.45 (s, 9H), 2.43-2.52 (m, 2H),2.70-2.80 (m, 2H), 3.70-3.78 (m, 2H), 6.03 (s, 1H), 6.97 (t, J=8.7 Hz,2H), 7.18 (q, J=8.7 5.4 Hz, 2H).

(E)-N-t-Butoxycarbonyl-3-chloro-2-(4-chlorophenylethyl)allylamine: (0.15g, 13%). Mp: 73-74° C. ¹H NMR (CDCl₃, 300 MHz) δ 1.45 (s, 9H), 2.41-2.52(m, 2H), 2.68-2.79 (m, 2H), 3.73 (d, J=5.4 Hz, 2H), 6.02 (s, 1H), 7.15(d, J=8.4 Hz, 2H), 7.25 (d, J=8.4 Hz, 2H).

(E)-N-t-Butoxycarbonyl-3-chloro-2-(4-methoxyphenylethyl)allylamine:(0.45 g, 40%). ¹H NMR (CDCl₃, 300 MHz) δ 1.45 (s, 9H), 2.28-2.47 (m,2H), 2.60-2.81 (m, 2H), 3.68-3.76 (m, 2H), 3.79 (s, 3H), 6.01 (s, 1H),6.83 (d, J=8.7 Hz, 2H), 7.15 (d, J=8.7 Hz, 2H).

(E)-N-t-Butoxycarbonyl-3-chloro-2-(4-ethoxyphenylethyl)allylamine: (1.18g, 44%). Mp: 78-79° C. ¹H NMR (CDCl₃, 300 MHz) δ 1.39 (t, J=6.6 Hz, 3H),1.44 (s, 9H), 2.36-2.52 (m, 2H), 2.63-2.76 (m, 2H), 3.61-3.79 (m, 2H),3.99 (q, J=6.9 Hz, 2H), 6.00 (s, 1H), 6.81 (d, J=8.4 Hz, 2H), 7.12 (d,J=8.4 Hz, 2H).

(E)-N-t-Butoxycarbonyl-3-chloro-2-(4-trifluoromethylphenylethyl)allylamine:(0.2 g, 27%). 1.44 (s, 9H), 2.46-2.56 (m, 2H), 2.79-2.89 (m, 2H),3.73-3.82 (m, 2H), 6.04 (s, 1H), 7.34 (d, J=8.7 Hz, 2H), 7.55 (d, J=8.7Hz, 2H).

(E)-N-t-Butoxycarbonyl-3-chloro-2-(4-n-butoxyphenylethyl)allylamine:(0.26 g, 19%). ¹H NMR (CDCl₃, 300 MHz) δ 0.97 (t, J=7.2 Hz, 3H), 1.45(s, 9H), 1.46-1.54 (m, 2H) 1.70-1.82 (m, 2H), 2.42-1.51 (m, 2H),2.66-2.75 (m, 2H), 3.72 (d, J=5.1 Hz, 2H), 3.94 (t, J=6.6 Hz, 2H), 6.02(s, 1H), 6.83 (d, J=8.7 Hz, 2H), 7.13 (d, J=8.7 Hz, 2H).

(E)-N-t-Butoxycarbonyl-3-chloro-2-(3-methylphenylethyl)allylamine: (0.61g, 36%). Mp: 73-74° C. ¹H NMR (CDCl₃, 300 MHz) δ 1.44 (s, 9H), 2.32 (s,3H), 2.43-2.52 (m, 2H), 2.67-2.76 (m, 2H), 3.73 (d, J=5.4 Hz, 2H), 6.01(s, 1H), 6.94-7.09 (m, 3H), 7.17 (t, J=7.8 Hz, 1H).

(E)-N-t-Butoxycarbonyl-3-chloro-2-(3-methoxyphenylethyl)allylamine: (0.8g, 36%). Mp: 66-67° C. ¹H NMR (CDCl₃, 300 MHz) δ 1.45 (s, 9H), 2.45-2.54(m, 2H), 2.70-2.79 (m, 2H), 3.74 (d, J=5.4 Hz, 2H), 3.80 (s, 3H), 6.02(s, 1H), 6.68-6.89 (m, 3H), 7.20 (t, J=7.2 Hz, 1H).

(E)-N-t-Butoxycarbonyl-3-chloro-2-(methylphenylthyl)allylamine: (0.99 g,60%). Mp: 53-54° C. ¹H NMR (CDCl₃, 300 MHz) δ 1.45 (s, 9H), 2.32 (s,3H), 2.43-2.52 (m, 2H), 2.68-2.76 (m, 2H), 3.68-3.77 (m, 2H), 6.02 (s,1H), 7.04-7.20 (m, 4H).

(E)-N-t-Butoxycarbonyl-3-chloro-2-(3-fluoro-5-trifluoromethylphenylethyl)-allylamine:(0.19 g, 46%). Mp: 59-60° C. ¹H NMR (CDCl₃, 300 MHz) δ 1.46 (s, 9H),2.46-2.56 (m, 2H), 2.79-2.88 (m, 2H), 3.79 (d, J=6.3 Hz, 2H), 6.06 (s,1H), 7.09-7.38 (m, 3H).

(Z)-N-t-Butoxycarbonyl-3-chloro-2-(4-fluorophenylethyl)allylamine:(0.095 g, 15%). ¹H NMR (CDCl₃, 300 MHz) δ 1.46 (s, 9H), 2.39 (t, J=8.7Hz, 2H), 2.74 (t, J=8.7 Hz, 2H), 4.0 (d, J=6.6 Hz, 2H), 5.86 (s, 1H),6.96 (t, J=8.7 Hz, 2H), 7.12 (t, J=8.7 5.4 Hz, 2H).

(Z)-N-t-Butoxycarbonyl-3-chloro-2-(4-chlorophenylethyl)allylamine: (0.05g, 5%). Mp: 76-77° C. ¹H NMR (CDCl₃, 300 MHz) δ 1.46 (s, 9H), 2.38 (t,J=8.7 Hz, 2H), 2.74 (t, J=8.7 Hz, 2H), 4.0 (d, J=6.6 Hz, 2H), 5.86 (s,1H), 7.09 (d, J=8.4 Hz, 2H), 7.24 (q, J=8.4 Hz, 2H).

(Z)-N-t-Butoxycarbonyl-3-chloro-2-(4-methoxyphenylethyl)allylamine:(0.15 g, 14%). ¹H NMR (CDCl₃, 300 MHz) δ 1.46 (s, 9H), 2.38 (t, J=7.8Hz, 2H), 2.70 (t, J=8.4 Hz, 2H), 3.79 (s, 3H), 3.98 (d, J=6.0 Hz, 2H),5.86 (s, 1H), 6.82 (d, J=8.4 Hz, 2H), 7.08 (d, J=8.4 Hz, 2H).

(Z)-N-t-Butoxycarbonyl-3-chloro-2-(4-ethoxyphenylethyl)allylamine: (0.29g, 11%). Mp: 70-72° C. ¹H NMR (CDCl₃, 300 MHz) δ 1.40 (t, J=6.6 Hz, 3H),1.46 (s, 9H), 2.38 (t, J=8.7 Hz, 2H), 2.70 (t, J=8.7 Hz, 2H), 3.92-4.06(m, 4H), 5.86 (s, 1H), 6.81 (d, J=8.7 Hz, 2H), 7.06 (d, J=8.7 Hz, 2H).

(Z)-N-t-Butoxycarbonyl-3-chloro-2-(4-n-butoxyphenylethyl)allylamine:(0.08 g, 6%). ¹H NMR (CDCl₃, 300 MHz) δ 0.97 (t, J=7.2 Hz, 3H), 1.46 (s,9H), 1.47-1.56 (m, 2H) 1.65-1.82 (m, 2H), 2.73 (t, J=8.7 Hz, 2H), 2.70(t, J=8.7 Hz, 2H), 3.93 (t, J=6.6 Hz, 2H), 3.99 (d, J=6.0 Hz, 2H), 5.86(s, 1H), 6.82 (d, J=8.7 Hz, 2H), 7.06 (d, J=8.7 Hz, 2H).

(Z)-N-t-Butoxycarbonyl-3-chloro-2-(3-methylphenylethyl)allylamine: (0.18g, 11%). Mp: 60-61° C. ¹H NMR (CDCl₃, 300 MHz) δ 1.45 (s, 9H), 2.31 (s,3H), 2.38 (t, J=7.8 Hz, 2H), 2.71 (t, J=7.8 Hz, 2H), 3.99 (d, J=6.0 Hz,2H), 5.88 (s, 1H), 6.92-7.02 (m, 3H), 7.16 (t, J=7.2 Hz, 1H).

(Z)-N-t-Butoxycarbonyl-3-chloro-2-(3-methoxyphenylethyl)allylamine:(0.28 g, 13%). Mp: 69-70° C. ¹H NMR (CDCl₃, 300 MHz) δ 1.46 (s, 9H),2.41 (t, J=8.4 Hz, 2H), 2.74 (t, J=8.4 Hz, 2H), 3.79 (s, 3H), 4.00 (d,J=6.0 Hz, 2H), 5.88 (s, 1H), 6.67-6.83 (m, 3H), 7.20 (t, J=7.8 Hz, 1H).

(Z)-N-t-Butoxycarbonyl-3-chloro-2-(4-methylphenylethyl)allylamine: (0.31g, 20%). Mp: 68-69° C. ¹H NMR (CDCl₃, 300 MHz) δ 1.46 (s, 9H), 2.32 (s,3H), 2.39 (t, J=8.4 Hz, 2H), 2.73 (t, J=8.4 Hz, 2H), 3.99 (d, J=5.4 Hz,2H), 5.88 (s, 1H), 7.05 (d, J=7.2 Hz, 2H), 7.09 (d, J=7.2 Hz, 2H).

(Z)-N-t-Butoxycarbonyl-3-chloro-2-(3-fluoro-5-trifluoromethylphenylethyl)-allylamine:(0.08 g, 18%). Mp: 71-72° C. ¹H NMR (CDCl₃, 300 MHz) δ 1.46 (s, 9H),2.42 (t, J=7.8 Hz, 2H), 2.84 (t, J=7.8 Hz, 2H), 4.03 (d, J=6.3 Hz, 2H),5.90 (s, 1H), 7.03-7.31 (m, 3H).

(E)-N-t-Butoxycarbonyl-3-chloro-2-(phenylethyl)allylamine: (0.25 g,23%). ¹H NMR (CDC₁₃, 300 MHz) δ 1.45 (s, 9H), 2.45-2.54 (m, 2H),2.71-2.82 (m, 2H), 3.72 (d, J=5.4 Hz, 2H), 6.02 (s, 1H), 7.11-7.41 (m,5H).

Example 7 Synthesis of Compounds of Formula I(E)-3-Fluoro-2-[2-(4-methoxyphenyl)-ethyl]-allylamine hydrochloride(I-102-E)

A mixture of (E)-isomer(E)-N-t-Butoxycarbonyl-3-fluoro-2-{2-(4-methoxyphenyl)ethyl}allylamine(0.235 g) in 20% TFA in CH₂Cl₂ (6 mL) was stirred at room temperaturefor 30 min. Then the TFA was evaporated to dryness, and the residue wasdissolved in water (20 mL) and washed with ether (2×10 mL). The aqueouslayer was basified to pH 10 by adding NaOH solution (5N). The resultingsolution was saturated with NaCl and extracted with ether (2×20 mL). Thecombined ether layers were then washed with brine, dried (Na₂SO₄),filtered, and concentrated to give an oil. The oil was then dissolved inether (5 mL), and a solution of HCl in ether (1.0M, 2 eq) was added. Awhite precipitate was formed. The solid was collected by filtration andwashed with ether to give the final (E)-allylamine I-102-E as HCl salt(0.186 g). m.p.: 154-155° C. ¹H NMR (CD₃OD, 300 MHz) δ 2.51 (t, J=8.4Hz, 2H), 2.72 (t, J=6.6 Hz, 2H), 3.41 (d, J=3 Hz, 1H), 3.76 (s, 3H),6.84 (dd, J=8.4 Hz, 2H), 6.85 (d, J=82 Hz, 1H), 7.14 (d, J=8.4 Hz, 1H).Cacld for C₁₂H₁₇ClFNO: C, 58.65; H, 6.97; N, 5.70. Found: C, 58.29; H,7.22; N, 6.07.

The compounds in the remainder of this example were synthesizedaccording to the procedure for I-102-E described above using theappropriate starting material synthesized from Examples 4 or 5.

(Z)-3-Fluoro-2- [2-(4-methoxyphenyl)-ethyl]-allylamine hydrochloride(I-102-Z) HCl salt was synthesized using the similar procedure andobtained as a white solid (0.140 g). m.p.: 94-95° C. ¹H NMR (CD₃OD, 300MHz) δ 2.33 (m, 2H), 2.70 (t, J=7.8 Hz, 2H), 3.62 (d, J=1.8 Hz, 2H),3.75 (s, 3H), 6.7 (d, J=84 Hz, 1H), 6.83 (d, J=8.4 Hz, 2H), 7.11 (d,J=8.4 Hz, 2H). Cacld for C₁₂H₁₇ClFNO*0.02H₂O: C, 58.57; H, 6.98; N,5.69. Found: C, 58.13; H, 7.22; N, 6.01.

(E)-3-Fluoro-2-(4-methoxybenzyl)-allylamine hydrochloride (I-1-E):177-178° C. ¹H NMR (CD₃OD, 300 MHz) δ 3.43 (d, J=2.4 Hz, 2H), 3.52 (brs, 2H), 3.79 (s, 3H), 6.95 (d, J=82.2 Hz, 1H), 6.97 (d, J=8.4 Hz, 2H),7.23 (d, J=8.4 Hz, 2H). Cacld for C₁₁H₁₅ClFNO: C, 57.02; H, 6.52; N,6.04. Found: C, 57.22; H, 6.42; N, 6.33.

(Z)-3-Fluoro-2-(4-methoxybenzyl)-allylamine hydrochloride (I-1-Z):160-161° C. ¹H NMR (CD₃OD, 300 MHz) δ 3.31 (d, J=3.6 Hz, 2H), 3.52 (d,J=2.4 Hz, 2H), 3.80 (s, 3H), 6.82 (d, J=82.2 Hz, 1H), 6.96 (d, J=8.4 Hz,2H), 7.23 (d, J=8.4 Hz, 2H). Cacld for C₁₁H₁₅CIFNO: C, 57.02; H, 6.52;N, 6.04. Found: C, 57.18; H, 6.36; N, 6.30.

(E)-3-Fluoro-2-(4-ethoxybenzyl)-allylamine hydrochloride (I-2-E): mp167-168° C. ¹H NMR (CD₃OD, 300 MHz) δ 1.37 (t, J=6.6 Hz, 3H), 3.33 (d,J=2.4 Hz, 2H), 3.50 (d, J=2.4 Hz, 2H), 4.00 (q, J=6.6 Hz, 2H), 6.86 (d,J=8.4 Hz, 2H), 7.01 (d, J=84.9 Hz, 1H), 7.14 (d, J=8.4 Hz, 2H). Cacldfor C₁₂H₁₇CIFNO: C, 58.66; H, 6.97; N, 5.70. Found: C, 58.42; H, 6.91;N, 5.74.

(Z)-3-Fluoro-2-(4-ethoxybenzyl)-allylamine hydrochloride (I-2-Z): mp153-154° C. ¹H NMR (CD₃OD, 300 MHz) δ 1.37 (t, J=6.6 Hz, 3H), 3.33 (brs, 2H), 3.49 (d, J=2.4 Hz, 2H), 4.00 (q, J=6.6 Hz, 2H), 6.83 (d, J=83.4Hz, 1H), 6.88 (d, J=8.4 Hz, 2H), 7.15 (d, J=8.4 Hz, 2H). Cacld forC₁₂H₁₇ClFNO: C, 58.66; H, 6.97; N, 5.70. Found: C, 58.32; H, 6.93; N,5.81.

(E)-3-Fluoro-2-(3,4-dimethoxybenzyl)-allylamine hydrochloride (I-6-E):mp 204-205° C. ¹H NMR (CD₃OD, 300 MHz) δ 3.31 (d, J==3.3 Hz, 2H), 3.41(br s, 2H), 3.70 (s, 6H), 6.84 (d, J=82.2 Hz, 1H), 6.69-7.01 (m, 3H).Cacld for C₁₂H₁₇ClFNO₂*0.05H₂O: C, 54.88; H, 6.56; N, 5.33. Found: C,54.42; H, 6.03; N, 5.48.

(Z)-3-Fluoro-2-(3,4-dimethoxybenzyl)-allylamine hydrochloride (I-6-Z):mp 220-221° C. ¹H NMR (CD₃OD, 300 MHz) δ 3.20 (s 2H), 3.44 (s 2H), 3.70(s, 6H), 6.70 (d, J=82.2 Hz, 1H), 6.72-6.93 (m, 3H). ESMS m/z 226(M+H)⁺.

Example 8 Alternate Synthesis of Compounds of Formula I(E)-3-Fluoro-2-(4-isopropoxybenzyl)allylamine hydrochloride (I-8-E)

To a solution ofE-N-t-butoxycarbonyl-3-fluoro-2-[2-(4-isopropoxyphenyl)ethyl]-allylamine(0.32 g, 0.99 mmol) in CH₂Cl₂ (5.0 mL) was added dropwisetrifluoroacetic acid (2.0 mL). The resulting mixture was stirred at roomtemperature for 20 min and then concentrated in vacuo to give asemisolid. This semisolid was dissolved in H₂O (20 mL) and washed withether (2×20 mL). The aqueous layer was basified with 2.0M NaOH solutionto pH 12 and then extracted with ether (3×30 mL). The combined organiclayers were dried over Na₂SO₄, filtered, and concentrated. The residuewas dissolved in ether (10 mL). To this solution was added a solution ofHCl in ether (2M, 2.0 mL). The solution was stirred at room temperaturefor 20 min. The precipitate was collected by filtration, washed withether 4-5 times, and then dried in vacuo. A white solid (0.24 g, 93%)was obtained. mp: 156-157° C. ¹H NMR (MeOH-d4, 300 MHz) δ 1.28 (d, J=6.0Hz, 6H), 3.35 (d, J=3.0 Hz, 2H), 3.50 (d, J=2.4 Hz, 2H), 4.55 (quintet,J=6.0 Hz, 1H), 6.85 (d, J=8.4 Hz, 2H), 7.00 (d, J=83.1 Hz, 1H), 7.14 (d,J=8.4 Hz, 2H). Calcd for C₁₃H₁₉ClFNO: C; 60.11, H; 7.37, N; 5.39. Found:C; 60.37, H; 7.28, N; 5.60.

The compounds in the remainder of this example were synthesizedaccording to the procedure for I-8-E described above using theappropriate starting material synthesized from Examples 4, 5, or 6.

(Z)-2-(4-Chlorobenzyl)-3-fluoro-allylamine hydrochloride (I-3: (0.21 g,86%): mp: 145-146° C. ¹H NMR (MeOH-d₄, 300 MHz) δ 3.38 (d, J=2.4 Hz,2H), 3.49 (d, J=1.8 Hz, 2H), 6.87 (d, J=82.8 Hz, 1H), 7.24 (d, J=8.4 Hz,2H), 7.34 (d, J=8.4 Hz, 2H). Calcd for C₁₀H₁₂Cl₂FN: C; 50.87, H; 5.12,N; 5.93. Found: C; 51.27, H; 5.41, N; 5.91.

(Z)-3-Fluoro-2-(3-chlorobenzyl)allylamine hydrochloride (I-4): (0.21 g,86%). Mp: 145-146° C. ¹H NMR (MeOD-d₃, 300 MHz) δ 3.39 (d, J=2.4 Hz,2H), 3.49 (d, J=1.8 Hz, 2H), 6.87 (d, J=82.8 Hz, 1H), 7.20-7.37 (m, 4H).Calcd for C₁₀H₁₂Cl₂FN: C; 50.87, H; 5.12, N; 5.93. Found: C; 51.27, H;5.41, N; 5.91.

(Z)-3-Fluoro-2-(3-methoxybenzyl)allylamine hydrochloride (I-5-Z): (0.048g, 47%): mp: 119.0-120.5° C. ¹H NMR (MeOH-d₄, 300 MHz) δ 3.37 (d, J=3.6Hz, 2H), 3.5 (br s, 2H), 3.79 (s, 3H), 6.79-6.86 (m, 3H), 6.88 (d,J=83.7 Hz, 1H), 7.22-7.29 (m, 1H). HRMS (ESI-TOF) Calcd for C₁₁H₁₄FNOH:196.1059. Found: 196.1049.

(Z)-3-Fluoro-2-(3,5-dimethoxybenzyl)allylamine hydrochloride (I-7):(0.05 g, 70%). Mp: 194-195° C. ¹H NMR (MeOD-d₃, 300 MHz) δ 3.31 (br s,2H), 3.50 (br s, 2H), 3.76 (s, 6H), 6.38-6.44 (m, 3H), 6.90 (d, J=83.4Hz, 1H). Calcd for C₁₂H₁₇ClFNO₂: C; 55.07, H; 6.55, N; 5.35. Found: C;55.29, H; 6.35, N; 5.54.

(Z)-3-Fluoro-2-(4-isopropoxybenzyl)allylamine hydrochloride (I-8-Z):(0.71 g, 98%) was obtained. mp: 147-148° C. ¹H NMR (MeOH-d4, 300 MHz) δ1.29 (d, J=6.0 Hz, 6H), 3.29-3.34 (m, 2H), 3.49 (d, J=2.4 Hz, 2H), 4.56(quintet, J=6.3 Hz, 1H), 6.84 (d, J=83.4 Hz, 1H), 6.87 (d, J=8.7 Hz,2H), 7.14 (d, J=8.4 Hz, 2H). Calcd for C₁₃H₁₉ClFNO: C; 60.11, H; 7.86,N; 5.39. Found: C; 60.22, H; 7.46, N; 5.50.

(Z)-3-Fluoro-2-(4-methylthiobenzyl)allylamine hydrochloride (I-9):(0.046 g, 50%): mp: 144-146° C. ¹H NMR (MeOH-d₄, 300 MHz) δ 2.46 (s,3H), 3.36 (dd, J=3.6, 1.2 Hz, 2H), 3.49 (br s, 2H), 6.86 (d, J=83.7 Hz,1H), 7.19 (d, J=8.4 Hz, 2H), 7.25 (d, J=8.4 Hz, 2H). Calcd forC₁₁H₁₅ClFNS*0.6H₂O: C; 51.10, H; 6.31, N; 5.42. Found: C; 51.16, H;6.33, N; 5.68.

(Z)-3-Fluoro-2-(3-methylthiobenzyl)allylamine hydrochloride (I-10):(0.04 g, 45%). Mp: 145-146° C. ¹H NMR (MeOD-d₃, 300 MHz) δ 2.47 (s, 3H),3.37 (d, J=4.5 Hz, 2H), 3.50 (d, J=2.4 Hz, 2H), 6.89 (d, J=84.9 Hz, 1H),7.13-7.33 (m, 4H). Calcd for C₁₁H₁₅ClFNS: C; 53.33, H; 6.10, N; 5.65.Found: C; 53.39, H; 6.45, N; 5.97.

(Z)-3-Fluoro-2-(4-methylbenzyl)allylamine hydrochloride (I-12): (0.62 g,96%). Mp 150-151° C. ¹H NMR (MeOD-d₃, 300 MHz) δ 2.31 (s, 3H), 3.35 (d,J=3.0 Hz, 2H), 3.48 (d, J=2.7 Hz, 2H), 6.84 (d, J=83.4 Hz, 2H),7.10-7.19 (m, 4H). Calcd for C₁₁H₁₅ClFN: C; 61.25, H; 7.01, N; 6.49.Found: C; 61.57, H; 7.27, N; 6.69.

(Z)-3-Fluoro-2-(3-methylbenzyl)allylamine hydrochloride (I-13): (0.03 g,42%). Mp: 118-119° C. ¹H NMR (MeODE-d₃, 300 MHz) δ 2.32 (s, 3H), 3.37(d, J=3.0 Hz, 2H), 3.49 (br s, 2H), 6.85 (d, J=83.1 Hz, 1H), 7.02-7.12(m, 3H), 7.20 (t, J=8.4 Hz, 1H). Calcd for C₁₁H₁₅ClFN: C; 61.25, H;7.01, N; 6.49. Found: C; 61.25, H; 6.76, N; 6.49.

(E)-3-Fluoro-2-(4-isopropylbenzyl)allylamine hydrochloride (I-14-E):(0.19 g, 96%): mp: 175-176° C. ¹H NMR (MeOH-d4, 300 MHz) δ 1.22 (d,J=7.4 Hz, 6H), 2.87 (quintet, J=6.9 Hz, 1H), 3.35 (d, J=3.0 Hz, 2H),3.54 (d, J=2.4 Hz, 2H), 7.00 (d, J=81.3 Hz, 1H), 7.15 (d, J=8.4 Hz, 2H),7.20 (d, J=8.4 Hz, 2H). Calcd for C₁₃H₁₉ClFN: C; 64.06, H; 7.86, N;5.75. Found: C; 64.44, H; 7.96, N; 5.83.

(Z)-3-Fluoro-2-(4-isopropylbenzyl)allylamine hydrochloride (I-14-Z):(0.19 g, 96%): mp: 175-176° C. ¹H NMR (MeOH-d4, 300 MHz) δ 1.23 (d,J=7.2 Hz, 6H), 2.88 (quintet, J=6.6 Hz, 1H), 3.35 (d, J=3.0 Hz, 2H),3.48 (d, J=2.7 Hz, 2H), 6.85 (d, J=83.7 Hz, 1H), 7.16 (d, J=8.1 Hz, 2H),7.21 (d, J=8.1 Hz, 2H). Calcd for C₁₃H₁₉ClFN: C; 64.06, H; 7.86, N;5.75. Found: C; 63.65, H; 7.92, N; 5.85.

(Z)-3-Fluoro-2-(4-tert-butylbenzyl)allylamine hydrochloride (I-15):(0.03 g, 20%): mp: 155-156° C. ¹H NMR (D₂O, 300 MHz) δ 1.12 (s, 9H),3.19 (d, J=3.0 Hz, 2H), 3.40 (d, J=2.4 Hz, 2H), 6.69 (d, J=83.4 Hz, 1H),7.10 (d, J=8.4 Hz, 2H), 7.32 (d, J=8.4 Hz, 2H). Calcd for C₁₄H₂₁ClFN: C;65.23, H; 8.21, N; 5.43. Found: C; 64.94, H; 8.12, N; 5.60.

(Z)-3-Fluoro-2-(4-phenylbenzyl)allylamine hydrochloride (I-16): (0.21 g,96%). Mp: 219-220° C. ¹H NMR (MeOD-d₃, 300 MHz) δ 3.45 (d, J=3.0 Hz,2H), 3.54 (d, J=2.4 Hz, 2H), 6.92 (d, J=83.7 Hz, 1H), 7.29-7.61 (m, 9H).Calcd for C₁₆H₁₇ClFN: C; 69.19, H; 6.17, N; 5.04. Found: C; 69.00, H;5.83, N; 5.24.

(Z)-3-Fluoro-2-(4-fluorobenzyl)allylamine hydrochloride (I-17): (0.15 g,84%). Mp: 139-140° C. ¹H NMR (MeOD-d₃, 300 MHz) δ 3.38 (d, J=3.6 Hz,2H), 3.49 (d, J=2.4 Hz, 2H), 6.86 (d, J=82.8 Hz, 1H), 7.06 (t, J=8.4 Hz,2H), 7.22-7.34 (m, 2H). Calcd for C10H₁₂CIF₂N: C; 54.68, H; 5.51, N;6.38. Found: C; 54.23, H; 5.39, N; 6.61.

(Z)-3-Fluoro-2-(3-trifluoromethylbenzyl)allylamine hydrochloride (I-18):(0.08 g, 80%). Mp: 161-162° C. ¹H NMR (MeOD-d₃, 300 MHz) δ 3.31 (d,J=3.6 Hz, 2H), 3.42 (d, J=2.4 Hz, 2H), 6.69 (d, J=82.2 Hz, 2H),7.35-7.55 (m, 4H). Calcd for C₁₁H₁₂ClF₄N: C; 48.99, H; 4.49, N; 5.19.Found: C; 49.18, H; 4.61, N; 5.31.

(Z)-3-Fluoro-2-(3-fluorobenzyl)allylamine hydrochloride (I-19-Z): (0.045g, 63%): mp: 120.5-121.5° C. ¹H NMR (MeOH-d₄, 300 MHz) δ 3.45 (d, J=3.0Hz, 2H), 3.51 (d, J=2.4 Hz, 2H), 6.90 (d, J=83.0 Hz, 1H), 6.94-7.15 (m,3H), 7.30-7.41 (m, 1H). Calcd for C₁₀H₁₂ClF₂N*0.2H₂O: C; 53.80, H; 5.84,N; 6.27. Found: C; 53.82, H; 5.84, N; 6.52.

(Z)-3-Fluoro-2-(3-fluoro-4-methylbenzyl)allylamine hydrochloride (I-20):(0.15 g, 49%). Mp: 160-161° C. ¹H NMR (MeOD-d₃, 300 MHz) δ 2.24 (s, 3H),3.37 (d, J=3.9 Hz, 2H), 3.49 (d, J=2.4 Hz, 2H), 6.88 (d, J=83.1 Hz, 1H),6.91-6.99 (m, 2H), 7.20 (t, J=8.7 Hz, 1H). Calcd for C₁₁H₁₄ClF₂N: C;56.54, H; 6.04, N; 5.99. Found: C; 56.43, H; 6.22, N; 6.19.

(Z)-3-Fluoro-2-(3-fluoro-4-methoxybenzyl)allylamine hydrochloride(I-21): (0.14 g, 67%). Mp: 170° C. (decompose). ¹H NMR (D₂O, 300 MHz) δ3.15 (br s, 2H), 3.40 (br s, 2H), 3.71 (s, 3H), 6.67 (d, J=83.1 Hz, 1H),6.85-7.02 (m, 3H). Calcd for C₁₁H₁₄ClF₂NO: C; 52.91, H; 5.65, N; 5.61.Found: C; 53.14, H; 5.58, N; 5.71.

(Z)-3-Fluoro-2-(4-fluoro-3-methylbenzyl)allylamine hydrochloride(I-22):(0.02 g, 42%). Mp: 158-159° C. ¹H NMR (MeOD-d₃, 300 MHz) δ 2.25(s, 3H), 3.37 (d, J=3.3 Hz, 2H), 3.50 (br s, 2H), 6.85 (d, J=83.1 Hz,1H), 6.94-7.18 (m, 3H). Calcd for C₁₁H₁₄ClF₂N*0.4H₂O: C; 51.34, H; 5.80,N; 5.44. Found: C; 51.01, H; 5.67, N; 5.59.

(Z)-3-Fluoro-2-(3-chloro-4-fluorobenzyl)allylamine hydrochloride (I-23):(0.08g, 45%). Mp: 163-164° C. ¹H NMR (MeOD-d₃, 300 MHz) δ 3.39 (d, J=3.0Hz, 2H), 3.50 (d, J=2.4 Hz, 2H), 6.91 (d, J=82.8 Hz, 1H), 7.19-7.27 (m,2H), 7.37-7.43 (m, 1H). Calcd for C₁₀H₁₁Cl₂F₂N: C; 47.27, H; 4.36, N;5.51. Found: C; 47.77, H; 4.50, N; 5.67.

(Z)-3-Fluoro-2-(2,5-difluorobenzyl)allylamine hydrochloride (I-24):(0.02 g, 51%). Mp: 105-106° C. ¹H NMR (MeOD-d₃, 300 MHz) δ 3.45 (d,J=3.6 Hz, 2H), 3.57 (d, J=2.4 Hz, 2H), 6.85 (d, J=82.8 Hz, 2H),7.00-7.24 (m, 3H). Calcd for C₁₀H₁₁ClF₃N: C; 50.54, H; 4.67, N; 5.89.Found: C; 50.45, H; 4.92, N; 5.97.

(Z)-3-Fluoro-2-(3-chloro-5-fluorobenzyl)allylamine hydrochloride (I-25):(0.09 g, 45%). Mp: 158-159° C. ¹H NMR (MeOD-d₃, 300 MHz) δ 3.43 (d,J=3.0 Hz, 2H), 3.51 (d, J=1.8 Hz, 2H), 6.94 (d, J=83.1 Hz, 1H),6.99-7.21 (m, 3H). ESMS m/z 218 (M+H)⁺.

(Z)-3-Fluoro-2-(2,4-difluorobenzyl)allylamine hydrochloride (I-26): (0.3g,27%). Mp: 130-131° C. ¹H NMR (MeOD-d₃, 300 MHz) δ 3.43 (d, J=3.0 Hz,2H), 3.56 (d, J=2.4 Hz, 2H), 6.80 (d, J=84.3 Hz, 1H), 6.95-7.04 (m, 2H),7.26-7.40 (m, 1H). Calcd for C₁₀H₁₁ClF₃N: C; 50.54, H; 4.67, N; 5.89.Found: C; 50.17, H; 5.06, N; 6.08.

(Z)-3-Fluoro-2-(3,5-dichlorobenzyl)allylamine hydrochloride (I-27):(0.06 g, 93%). Mp: 184-185° C. ¹H NMR (MeOD-d₃, 300 MHz) δ 3.40 (d,J=3.6 Hz, 2H), 3.51 (d, J=2.4 Hz, 2H), 6.94 (d, J=82.5 Hz, 1H),7.24-7.29 (m, 2H), 7.36-7.39 (m, 1H). Calcd for C₁₀H₁₁Cl₃FN*0.4H₂O: C;43.24, H; 4.28, N; 5.04. Found: C; 43.23, H; 4.21, N; 5.26.

(Z)-3-Fluoro-2-(3,4-difluorobenzyl)allylamine hydrochloride (I-28): (0.2g, 18%). Mp: 141-142° C. ¹H NMR (MeOD-d₃, 300 MHz) δ 3.38 (d, J=3.0 Hz,2H), 3.51 (d, J=2.4 Hz, 2H), 6.90 (d, J=82.8 Hz, 1H), 7.02-7.31 (m, 3H).Calcd for C₁₀H₁₁ClF₃N: C; 50.54, H; 4.67, N; 5.89. Found: C; 50.35, H;5.00, N; 6.07.

(Z)-3-Chloro-2-(4-fluorophenylethyl)allylamine trifluoroacetate (I-31):(0.09 g, 90%). Mp: 69-70° C. ¹H NMR (MeOD-d₃, 300 MHz) δ 2.53 (t, J=7.8Hz, 2H), 2.79 (t, J=7.8 Hz, 2H), 3.77 (br s, 2H), 6.34 (s, 1H), 7.01 (t,J=8.4 Hz, 2H), 7.25 (q, J=8.4, 3.0 Hz, 2H). Calcd for C₁₃H₁₄ClF₄NO₂: C;47.65, H; 4.31, N; 4.27. Found: C; 48.09, H; 4.33, N; 4.47.

(Z)-3-Chloro-2-(4-chlorophenylethyl)allylamine trifluoroacetate (I-32):(0.03 g, 60%). Mp: 89-90° C. ¹H NMR (MeOD-d₃, 300 MHz) δ 2.53 (t, J=8.1Hz, 2H), 2.79 (t, J=8.1 Hz, 2H), 3.77 (br s, 2H), 6.33 (s, 1H), 7.19 (d,J=8.7 Hz, 2H), 7.28 (d, J=8.7 Hz, 2H). Calcd for C₁₃H₁₄C₁₂F₃NO₂: C;45.34, H; 4.10, N; 4.07. Found: C; 45.67, H; 4.11, N; 4.11.

(Z)-3-Chloro-2-(4-methoxyphenylethyl)allylamine hydrochloride (I-33):(0.02 g, 40%). Mp: 123-124° C. ¹H NMR (D₂O, 300 MHz) δ 2.27-2.40 (m,2H), 2.54-2.65 (m, 2H), 3.61 (br s, 2H), 3.64 (s, 3H), 6.06 (s, 1H),6.79 (d, J=8.4 Hz, 2H), 7.05 (d, J=8.4 Hz, 2H). Calcd for C₁₂H₁₇Cl₂NO:C; 54.97, H; 6.54, N; 5.34. Found: C; 54.84, H; 6.41, N; 5.37.

(Z)-3-Chloro-2-(4-ethoxyphenylethyl)allylamine hydrochloride (I-34):(0.2 g, 85%). Mp: 160-162° C. ¹H NMR (MeOD-d₃, 300 MHz) δ 1.36 (t, J=7.2Hz, 3H), 2.46-2.55 (m, 2H), 2.68-2.82 (m, 2H), 3.74 (br s, 2H), 3.98 (q,J=7.2 Hz, 2H), 6.32 (s, 1H), 6.82 (d, J=8.4 Hz, 2H), 7.10 (d, J=8.4 Hz,2H). Calcd for C₁₃H₁₉Cl₂NO: C; 56.53, H; 6.93, N; 5.07. Found: C; 56.49,H; 6.80, N; 5.14.

(Z)-3-Chloro-2-(4-n-butoxyphenylethyl)allylamine hydrochloride (I-36):(0.06 g, 94%). Mp: 133-134° C. ¹H NMR (MeOD-d₃, 300 MHz) δ 0.97 (t,J=7.2 Hz, 3H), 1.41-1.57 (m 2H), 1.65-1.79 (m, 2H), 2.45-2.58 (m, 2H),2.67-2.80 (m, 2H), 3.73 (br s, 2H), 3.93 (t, J=6.0 Hz, 2H), 6.33 (s,1H), 6.83 (d, J=8.4 Hz, 2H), 7.10 (d, J=8.4 Hz, 2H). Calcd forC₁₅H₂₃Cl₂NO: C; 59.21, H; 7.62, N; 4.60. Found: C; 59.24, H; 7.55, N;4.52.

(Z)-3-Chloro-2-(3-methylphenylethyl)allylamine hydrochloride (I-37):(0.06 g, 48%). Mp: 102-103° C. ¹H NMR (MeOD-d₃, 300 MHz) δ 2.30 (s, 3H),2.49-2.57 (m, 2H), 2.72-2.80 (m, 2H), 3.75 (br s, 2H), 6.34 (s, 1H),6.97-7.06 (m, 3H), 7.16 (t, J=7.2 Hz, 1H). Calcd for C₁₂H₁₇Cl₂N: C;58.55, H; 6.96, N; 5.69. Found: C; 58.46, H; 6.64, N; 5.57.

(Z)-3-Chloro-2-(3-methoxyphenylethyl)allylamine hydrochloride (I-38):(0.14 g, 69%). Mp: 139-140° C. ¹H NMR (MeOD-d₃, 300 MHz) δ 2.50-2.58 (m,2H), 2.73-2.82 (m, 2H), 3.75 (br s, 2H), 3.77 (s, 3H), 6.35 (s, 1H),6.73-6.82 (m, 3H), 7.19 (t, J=8.7 Hz, 1H). Calcd for C₁₂H₁₇Cl₂NO: C;54.97, H; 6.54, N; 5.34. Found: C; 55.06, H; 6.29, N; 5.39.

(Z)-3-Chloro-2-(4-methylphenylethyl)allylamine hydrochloride (I-39):(0.01 g, 40%). Mp: 135° C. (decompose). ¹H NMR (D₂O, 300 MHz) δ 2.12 (s,3H), 2.30-2.40 (m, 2H), 2.56-2.66 (m, 2H), 3.62 (br s, 2H), 6.06 (s,1H), 6.95-7.10 (m, 4H). Calcd for C₁₂H₁₇Cl₂N: C; 58.55, H; 6.96, N;5.69. Found: C; 58.75, H; 6.77, N; 5.38.

(Z)-3-Chloro-2-(3-fluoro-5-trifluoromethylphenylethyl)allylaminetrifluoroacetate (I-40): (0.07 g, 93%). Mp: 51-52° C. ¹H NMR (MeOD-d₃,300 MHz) δ 2.53-2.61 (m, 2H), 2.87-2.95 (m, 2H), 3.82 (s, 2H), 6.42 (s,1H), 7.27-7.35 (m, 2H), 7.42 (s, 1H). Calcd for C₁₄H₁₃ClF₇NO₂: C; 42.49,H; 3.31, N; 3.54. Found: C; 42.59, H; 3.35, N; 3.58.

(E)-3-Chloro-2-(phenylethyl)allylamine hydrochloride (I-41): (0.15 g,80%). Mp: 97-98° C. ¹H NMR (D₂O, 300 MHz) δ 2.47 (t, J=8.1 Hz, 2H), 2.67(t, J=8.1 Hz, 2H), 3.75 (br s, 2H), 6.20 (s, 1H), 7.05-7.29 (m, 5H).Calcd for C₁₁H₁₅Cl₂N: C; 56.91, H; 6.51, N; 6.03. Found: C; 57.12, H;6.62, N; 5.87.

(E)-3-Chloro-2-(4-fluorophenylethyl)allylamine trifluoroacetate (I-42):(0.34 g, 90%). Mp: 52-53° C. ¹H NMR (MeOD-d₃, 300 MHz) δ 2.57-2.64 (m,2H), 2.74-2.83 (m, 2H), 3.55 (br s, 2H), 6.45 (s, 1H), 7.01 (t, J=8.4Hz, 2H), 7.25 (q, J=8.4, 3.0 Hz, 2H). Calcd for C₁₃H₁₄ClF₄NO₂: C; 47.65,H; 4.31, N; 4.27. Found: C; 47.81, H; 4.12, N; 4.37.

(E)-3-Chloro-2-(4-chlorophenylethyl)allylamine trifluoroacetate (I-43):(0.13 g, 90%). Mp: 68-70° C. ¹H NMR (MeOD-d₃, 300 MHz) δ 2.56-2.66 (m,2H), 2.72-2.81 (m, 2H), 3.55 (br s, 2H), 6.44 (s, 1H), 7.22 (d, J=8.7Hz, 2H), 7.28 (d, J=8.7 Hz, 2H). Calcd for C₁₃H₁₄Cl₂F₃NO₂: C; 45.34, H;4.10, N; 4.07. Found: C; 45.56, H; 4.12, N; 4.11.

(E)-3-Chloro-2-(4-methoxyphenylethyl)allylamine hydrochloride (I-44):(0.2 g, 80%). Mp: 138° C. (decompose). ¹H NMR (D₂O, 300 MHz) δ 2.40-2.49(m, 2H), 2.58-2.67 (m, 2H), 3.38 (br s, 2H), 3.66 (s, 3H), 6.21 (s, 1H),6.80 (d, J=8.4 Hz, 2H), 7.11 (d, J=8.4 Hz, 2H). Calcd for C₁₂H₁₇Cl₂NO:C; 54.97, H; 6.54, N; 5.34. Found: C; 55.14, H; 6.51, N; 5.67.

(E)-3-Chloro-2-(4-ethoxyphenylethyl)allylamine hydrochloride (I-45):(0.9 g, 82%). Mp: 104-106° C. ¹H NMR (MeOD-d₃, 300 MHz) δ 1.36 (t, J=7.2Hz, 3H), 2.54-2.62 (m, 2H), 2.68-2.77 (m, 2H), 3.49 (br s, 2H), 3.99 (q,J=7.2 Hz, 2H), 6.43 (s, 1H), 6.82 (d, J=8.4 Hz, 2H), 7.13 (d, J=8.4 Hz,2H). Calcd for C₁₃H₁₉Cl₂NO: C; 56.53, H; 6.93, N; 5.07. Found: C; 56.62,H; 6.94, N; 5.29.

(E)-3-Chloro-2-(4-trifluoromethylphenylethyl)allylamine hydrochloride(I-46): (0.1 g, 70%). Mp: 89-90° C. ¹H NMR (D₂O, 300 MHz) δ 2.49 (t,J=8.1 Hz, 2H), 2.73 (t, J=8.1 Hz, 2H), 3.40 (br s, 2H), 6.21 (s, 1H),7.27 (d, J=7.8 Hz, 2H), 7.48 (d, J=7.8 Hz, 2H). Calcd for C₁₂H₁₄Cl₂F₃N:C; 48.02, H; 4.70, N; 4.67. Found: C; 47.84, H; 4.51, N; 4.70.

(E)-3-Chloro-2-(4-n-butoxyphenylethyl)allylamine hydrochloride (I-47):(0.9 g, 82%). Mp: 132-33° C. ¹H NMR (MeOD-d₃, 300 MHz) δ 0.97 (t, J=7.2Hz, 3H), 1.44-1.56 (m 2H), 1.67-1.79 (m, 2H), 2.54-2.62 (m, 2H),2.68-2.77 (m, 2H), 3.48 (br s, 2H), 3.93 (t, J=6.9 Hz, 2H), 6.43 (s,1H), 6.83 (d, J=8.4 Hz, 2H), 7.15 (d, J=8.4 Hz, 2H). Calcd forC₁₅H₂₃Cl₂NO: C; 59.21, H; 7.62, N; 4.60. Found: C; 59.54, H; 7.45, N;4.42.

(E)-3-Chloro-2-(3-methylphenylethyl)allylamine hydrochloride (I-48):(0.23 g, 48%). Mp: 95-97° C. ¹H NMR (MeOD-d₃, 300 MHz) δ 2.31 (s, 3H),2.57-2.66 (m, 2H), 2.71-2.79 (m, 2H), 3.51 (br s, 2H), 6.45 (s, 1H),6.98-7.10 (m, 3H), 7.16 (t, J=7.2 Hz, 1H). Calcd for C₁₂H₁₇Cl₂N: C;58.55, H; 6.96, N; 5.69. Found: C; 58.65, H; 6.87, N; 5.58.

(E)-3-Chloro-2-(3-methoxyphenylethyl)allylamine hydrochloride (I-49):(0.36 g, 62%). Mp: 85-87° C. ¹H NMR (MeOD-d₃, 300 MHz) δ 2.58-2.67 (m,2H), 2.73-2.81 (m, 2H), 3.52 (br s, 2H), 3.77 (s, 3H), 6.46 (s, 1H),6.72-6.88 (m, 3H), 7.19 (d, J=8.1 Hz, 1H). Calcd for C₁₂H₁₇Cl₂NO: C;54.97, H; 6.54, N; 5.34. Found: C; 54.89, H; 6.17, N; 5.33.

(E)-3-Chloro-2-(4-methylphenylethyl)allylamine hydrochloride (I-50):(0.04 g, 60%). Mp: 124-125° C. ¹H NMR (D₂O, 300 MHz) δ 2.13 (s, 3H),2.39-2.49 (m, 2H), 2.58-2.68 (m, 2H), 3.38 (br s, 2H), 3.66 (s, 3H),6.20 (s, 1H), 6.95-7.20 (m, 4H). Calcd for C₁₂H₁₇Cl₂N: C; 58.55, H;6.96, N; 5.69. Found: C; 58.65, H; 6.87, N; 5.58.

(E)-3-Chloro-2-(3-fluoro-5-trifluoromethylphenylethyl)allylaminehydrochloride (I-51): (0.13 g, 96%). Mp: 96-97° C. ¹H NMR (MeOD-d₃, 300MHz) δ 2.67 (t, J=8.7 Hz, 2H), 2.91 (t, J=8.7 Hz, 2H), 3.65 (s, 2H),6.50 (s, 1H), 7.27-7.39 (m, 2H), 7.43 (s, 1H). Calcd for C₁₂H₁₃Cl₂F₄N:C; 45.30, H; 4.12, N; 4.40. Found: C; 45.70, H; 4.01, N; 4.44.

(Z)-3-Fluoro-2-(3-fluorophenylethyl)allylamine trifluoroacetate(I-100-E): (0.08 g, 92%). Mp: 47-48° C. ¹H NMR (MeOD-d₃, 300 MHz) δ2.32-2.42 (m, 2H), 2.73-2.83 (m, 2H), 3.65 (d, J=1.8 Hz, 2H), 6.74 (d,J=83.7 Hz, 1H), 6.89-7.08 (m, 3H), 7.24-7.36 (m, 1H). Calcd forC₁₃H₁₄F₅NO₂: C; 50.15, H; 4.53, N; 4.5. Found: C; 49.86, H; 4.64, N;4.46.

(E)-3-Fluoro-2-(3-fluorophenylethyl)allylamine trifluoroacetate(I-100-Z): (0.13 g, 98%). Mp: 72-73° C. ¹H NMR (MeOD-d₃, 300 MHz) δ2.47-2.56 (m, 2H), 2.75-2.83 (m, 2H), 3.45 (d, J=2.7 Hz, 2H), 6.85 (d, J=82.4 Hz, 1H), 6.87-7.03 (m, 3H), 7.24-7.34 (m, 1H). Calcd forC₁₃H₁₄F₅NO₂: C; 50.15, H; 4.53, N; 4.5. Found: C; 50.04, H; 4.76, N;4.92.

(E)-3-Fluoro-2-(3-fluoro-5-trifluoromethylphenylethyl)allylaminetrifluoroacetate (I-109-E): (0.29 g, 96%). Mp: 58-59° C. ¹H NMR(MeOD-d₃, 300 MHz) δ 2.51-2.59 (m, 2H), 2.84-2.93 (m, 2H), 3.52 (br s,2H), 6.87 (d, J=82.2 Hz, 1H), 7.25-7.34 (m, 2H), 7.40 (s, 1H). Calcd forC₁₄H₁₃F₈NO₂: C; 44.34, H; 3.45, N; 3.69. Found: C; 44.32, H; 3.30, N;3.88.

(Z)-3-Fluoro-2-(3-fluoro-5-trifluoromethylphenylethyl)allylaminetrifluoroacetate (I-109-Z): (0.15 g, 94%). Mp: 56-57° C. ¹H NMR(MeOD-d₃, 300 MHz) δ 2.35-2.46 (m, 2H), 2.82-2.91 (m, 2H), 3.70 (br s,2H), 6.78 (d, J=83.7 Hz, 1H), 7.26-7.36 (m, 3H), 7.41 (s, 1H). Calcd forC₁₄H₁₃F₈NO₂: C; 44.34, H; 3.45, N; 3.69. Found: C; 43.98, H; 3.16, N;3.71.

Example 9 Synthesis of Compound I-11

(Z)-N-t-Butoxycarbonyl-3-fluoro-2-(4-methanesulfonylbenzyl)allylamine:To a cooled solution of(Z)-N-t-Butoxycarbonyl-3-fluoro-2-(3-methylthiobenzyl)allylamine (0.36g, 1.2 mmol) in EtOAc (5 mL) was added a solution of H₅IO₆/CrO₃ inacetonitrile (0.2 mL). The resulting mixture was stirred at −35° C. for1 hour, quenched with saturated Na₂SO₃ solution (2 mL) and filtered. Thesolid was washed with EtOAc and filtered. The filtrate was washed withsaturated Na₂SO₃ solution (2×10 mL), brine (20 mL), dried (MgSO4),filtered, and concentrated. The residue was purified on columnchromatography (silica gel, 40% EtOAc/hexane) to give an oil (0.34 g,77%). ¹H NMR (CDCl₃, 300 MHz) δ 1.43 (s, 9H), 3.05 (s, 3H), 3.35 (d,J=3.0 Hz, 2H), 3.78 (br s, 2H), 6.53 (d, J=82.8 Hz, 1H), 7.45 (d, J=8.4Hz, 2H), 7.90 (d, J=8.4 Hz, 1H).

(Z)-3-fluoro-2-(4-methanesulfonylbenzyl)allylamine trifluoroacetate(I-11): A mixture of(Z)-N-t-Butoxycarbonyl-3-fluoro-2-(3-methanesulfonylbenzyl)allylamine(0.34 g, 0.62 mmol) in 20% TFA/CH₂Cl₂ (5 mL) was stirred at roomtemperature for 30 min, concentrated. The residue was washed with ether.The solid was collected by filtration (0.02 g, 45%). Mp: 49-50° C. ¹HNMR (MeOD-d₃, 300 MHz) δ 3.11 (s, 3H), 3.51 (br s, 2H), 3.54 (d, J=3.6Hz, 2H), 6.94 (d, J=83.1 Hz, 1H), 7.56 (d, J=8.1 Hz, 2H), 7.95 (d, J=8.1Hz, 2H). ESMS m/z 244 (M+H)⁺.

Example 10 Methoxy Deprotections(Z)-3-Fluoro-2-(4-hydroxylbenzyl)allylamine hydrobromide (I-29)

To a solution of(Z)-N-t-Butoxycarbonyl-3-fluoro-2-(4-methoxybenzyl)allylamine (0.4 g,1.35 mmol) in dichloromethane (20 mL) was added a solution of BBr₃ indichloromethane (1.0 M, 3.37 mL, 3.37 mmol). The reaction mixture wasstirred at room temperature for 45 min, and concentrated in vacuo. Theresidue was purified by flash column chromatography (silica gel, 10-12%MeOH/CH₂Cl₂ with 0.1 % NH₄OH) to give a solid (0.15 g, 62%). Mp:176-177° C. ¹H NMR (MeOD-d₃, 300 MHz) δ 3.17 (d, J=3.6 Hz, 2H), 3.43 (d,J=2.7 Hz, 2H), 6.69 (d, J=83.7 Hz, 1H), 6.75 (d, J=8.4 Hz, 2H), 7.04 (d,J=8.4 Hz, 2H). Calcd for C₁₀H₁₃BrFNO*0.18H₂O: C; 45.26, H; 5.07, N;5.28. Found: C; 44.88, H; 4.85, N; 5.52.

(Z)-3-Fluoro-2-(3-hydroxylbenzyl)allylamine citrate (I-30) was obtainedusing the same procedure as described above: (0.04 g, 45%). Mp: 145-146°C. ¹H NMR (MeOD-d₃, 300 MHz) δ 3.17-3.41 (m, 6H), 3.50 (br s, 2H),6.62-6.77 (m, 3H), 6.87 (d, J=83.1 Hz, 1H), 7.09-7.21 (m, 1H).

Example 11 Aminoketone Deprotections

The compounds in this example were deprotected according to theprocedure of either Example 7 or 8.

4-(4-Fluorophenyl)-2-oxobutylamine trifluoroacetate (IV-1): (0.2 g,89%). Mp: 103-104° C. ¹H NMR (MeOD-d₃, 300 MHz) δ 2.78-2.99 (m, 4H),3.92 (s, 2H), 6.99 (t, J=8.7 Hz, 2H), 7.19-7.28 (m, 2H). Calcd forC₁₂H₁₃F₄NO₃: C; 48.82, H; 4.44, N; 4.74. Found: C; 49.13, H; 4.35, N;4.80.

4-(4-Chlorophenyl)-2-oxobutylamine trifluoroacetate (IV-2): (0.73 g,87%). Mp: 125-126° C. ¹H NMR (MeOD-d₃, 300 MHz) δ 2.83-2.95 (m, 4H),3.91 (s, 2H), 7.20 (d, J=8.7 Hz, 2H), 7.26 (d, J=8.7 Hz, 2H). Calcd forC₁₂H₁₃IF₃NO₃: C; 46.24, H; 4.20, N; 4.49. Found: C; 46.22, H; 4.32, N;4.49.

4-(4-Methoxyphenyl)-2-oxobutylamine trifluoroacetate (IV-3): (1.02 g,97%). Mp: 108-109° C. ¹H NMR (MeOD-d₃, 300 MHz) δ 2.77-2.90 (m, 4H),3.74 (s, 3H), 3.89 (s, 2H), 6.82 (d, J=8.4 Hz, 2H), 7.12 (d, J=8.4 Hz,2H). Calcd for C₁₃H₁₆ClF₃NO₄: C; 46.24, H; 4.20, N; 4.49. Found: C;46.22, H; 4.32, N; 4.49.

4-(3-Methoxyphenyl)-2-oxobutylamine hydrochloride (IV-7): (0.35 g, 21%).Mp: 120-122° C. ¹H NMR (MeOD-d₃, 300 MHz) δ 2.68-2.91 (m, 4H), 3.73 (s,3H), 3.91 (s, 2H), 6.68-6.82 (m, 3H), 7.12-7.21 (m, 1H). Calcd forC₁₁H₁₆ClFNO₂: C; 46.24, H; 4.20, N; 4.49. Found: C; 46.22, H; 4.32, N;4.49.

4-(3-Fluoro-5-trifluoromethylphenyl)-2-oxobutylamine trifluoroacetate(IV-10): (0.5 g, 64%). Mp: 95-96° C. ¹H NMR (MeOD-d₃, 300 MHz) δ2.83-2.95 (m, 4H), 3.91 (s, 2H), 7.20 (d, J=8.7 Hz, 2H), 7.26 (d, J=8.7Hz, 2H). Calcd for C₁₃H₁₂F₇NO₃: C; 42.98, H; 3.33, N; 3.86. Found: C;43.25, H; 3.22, N; 3.85.

Example 12 Synthesis of Ester Precursors to Compounds of Formula IIMethyl 3-fluoro-5-trifluorophenylacetate

A mixture of 3-Fluoro-5-trifluoromethyl-phenylacetic acid (4.72 g, 21.2mmol) and concentrated HCl (1.2 mL) in MeOH (50 mL) was refluxed for 2.5h, then concentrated in vacuo. The residue was partitioned between 100mL of EtOAc and washed sequentially with 0.5N aqueous NaOH (30 mL), 2%NaHCO₃ solution (30 mL), and brine (30 mL). The EtOAc layer was dried(Na₂SO₄), filtered, and concentrated to provide 5.01 g (quantitative) ofmethyl 3-fluoro-5-trifluoromethyl-phenylaceiate as a colorless oil: ¹HNMR (CDCl₃, 300 MHz) δ 3.69 (s, 2H), 3.73 (s, 3H), 7.21-7.73 (m, 3H).

The compounds in the remainder of this example were synthesizedaccording to the procedure for Methyl 3-fluoro-5-trifluorophenylacetatedescribed above using the appropriate starting material.

Methyl 3-trifluoromethylphenylacetate: (5.26 g, 99%). ¹H NMR (CDCl₃, 300MHz) δ 3.70 (s, 2H), 3.72 (s, 3H), 7.56-7.73 (m, 4H).

Methyl 4-methoxyphenylacetate: (5.38 g, 99%). ¹H NMR (CDCl₃, 300 MHz) δ3.57 (s, 2H), 3.69 (s, 3H), 3.80 (s, 3H), 6.87 (d, J=8.1 Hz, 2H), 7.20(d, J=8.1 Hz, 2H).

Methyl 4-fluorophenylacetate: (4.8 g, 88%). ¹H NMR (CDCl₃, 300 MHz) δ3.60 (s, 2H), 3.70 (s, 3H), 7.01 (t, J=8.4 Hz, 2H), 7.26 (d, J=8.4 Hz,2H).

Methyl 3-methylphenylacetate: (5.52 g, 98%). ¹H NMR (CDCl₃, 300 MHz) δ2.34 (s, 3H), 3.59 (s, 2H), 3.69 (s, 3H), 6.96-7.32 (m, 4H).

Methyl 3-fluorophenylacetate: (5.24 g, 96%). ¹H NMR (CDCl₃, 300 MHz) δ3.63 (s, 2H), 3.71 (s, 3H), 6.91-7.11 (m, 3H), 7.22-7.37 (m, 1H).

Methyl 3-methoxyphenylacetate: (5.38 g, 99%). ¹H NMR (CDCl₃, 300 MHz) δ3.61 (s, 2H), 3.70 (s, 3H), 3.81 (s, 3H), 6.77-6.92 (m, 3H), 7.19-7.31(m, 1H).

Methyl 3-trifluoromethoxyphenylacetate: (5.07 g, 96%). ¹H NMR (CDCl₃,300 MHz) δ 3.65 (s, 2H), 3.71 (s, 3H), 7.10-7.29 (m, 3H), 7.35 (t, J=7.8Hz, 1H).

Methyl 3,5-ditrifluoromethylphenylacetate: (5.07 g, 96%). ¹H NMR (CDCl₃,300 MHz) δ 3.70 (s, 2H), 3.72 (s, 3H), 7.68 (s, 2H), 7.82 (s, 1H).

Methyl 3-methylthiophenylacetate: (4.1 g, 95%). ¹H NMR (CDCl₃, 300 MHz)δ 2.48 (s, 3H), 3.60 (s, 2H), 3.70 (s, 3H), 7.02-7.08 (m, 1H), 7.13-7.21(m, 2H), 7.21-7.30 (m, 1H).

Methyl 3-trifluoromethylthiophenylacetate: (5.1 g, 95%). ¹H NMR (CDCl₃,300 MHz) δ 3.67 (s, 2H), 3.71 (s, 3H), 7.37-7.46 (m, 2H), 7.54-7.63 (m,2H).

Methyl 2-methoxyphenylacetate: (5.35 g, 99%). ¹H NMR (CDCl₃, 300 MHz) δ3.64 (s, 2H), 3.69 (s, 3H), 3.82 (s, 3H), 6.83-6.99 (m, 2H), 7.14-7.33(m, 2H).

Methyl 3-(3-methoxyphenyl)propionate: (5.17 g, 99%). ¹H NMR (CDCl₃, 300MHz) δ 2.63 (t, J=8.7 Hz, 2H), 2.93 (t, J=8.7 Hz, 2H), 3.68 (s, 3H),3.80 (s, 3H), 6.72-6.87 (m, 3H), 7.16-7.31 (m, 1H).

Example 13 Synthesis of Aldehyde Precursors to Compounds of Formula II3-Fluoro-5-trifluoromethyl-phenylacetaldehyde

To a solution of 5.0 g (21.2 mmol) ofmethyl-3-fluoro-5-trifluorophenylacetate in 21.2 mL of CH₂Cl₂ and 10.6mL of hexane, cooled to −70° C. in an argon atmosphere, was added 17.0mL (25.4 mmol) of a 1.5M solution of DIBAL-H in toluene overapproximately two minutes. The mixture was allowed to warm to −50° C.over 1 h, and 21.2 mL of MeOH was added, followed by 14 mL of 6 N HCland 21.2 mL of H₂O. The mixture was extracted with EtOAc, and the EtOAclayer was washed sequentially with H₂O and brine, dried (MgSO₄),filtered, and concentrated. The residue was purified by silica gelchromatography (¼ EtOAc/hexane) to provide 4.10 g (94%) of product as acolorless oil: ¹H NMR (CDCl₃) δ 3.82 (s, 2H), 7.11-7.31 (m, 3H), 9.80(s, 1H).

The compounds in the remainder of this example were synthesizedaccording to the procedure for3-Fluoro-5-trifluoromethyl-phenylacetaldehyde described above using theappropriate starting material from Example 12.

3-Trifluormethylphenylacetaldehyde: (3.38 g, 75%). ¹H NMR (CDCl₃, 300MHz) δ 3.80 (s, 2H), 7.37-7.65 (m, 4H), 9.80 (s, 1H).

4-Methoxyphenylacetaldehyde: (1.44 g, 67%). ¹H NMR (CDCl₃, 300 MHz) δ3.63 (s, 2H), 3.80 (s, 3H), 6.91 (d, J=8.4 Hz, 2H) 7.14 (d, J=8.4 Hz,2H), 9.73 (s, 1H).

4-Fluorophenylacetaldehyde: (1.23 g, 75%). ¹H NMR (CDCl₃, 300 MHz) δ3.69 (s, 2H), 7.06 (t, J=8.4 Hz, 2H) 7.15-7.24 (m, 2H), 9.75 (s, 1H).

3-Methylphenylacetaldehyde: (1.1 g, 65%). ¹H NMR (CDCl₃, 300 MHz) δ 2.36(s, 3H), 3.65 (s, 2H), 6.97-7.39 (m, 4H), 9.74 (s, 1H).

3-Fluorophenylacetaldehyde: (1.4 g, 73%). ¹H NMR (CDCl₃, 300 MHz) δ 3.71(s, 2H), 6.89-7.10 (m, 3H), 7.28-7.41 (m, 1H), 9.76 (s, 1H).

3-Methoxyphenylacetaldehyde: (1.14 g, 58%). ¹H NMR (CDCl₃, 300 MHz) δ3.35 (s, 2H), 3.81 (s, 3H), 6.73-6.92 (m, 3H) 7.24-7.36 (m, 1H), 9.74(s, 1H).

3-Trifluoromethoxyphenylacetaldehyde: (1.49 g, 67%). ¹H NMR (CDCl₃, 300MHz) δ 3.75 (s, 2H), 7.08-7.19 (m, 3H), 7.41 (t, J=7.8 Hz, 1H)., 9.78(s, 1H).

3,5-Ditrifluoromethylphenylacetaldehyde: (1.7 g, 75%). Mp: 50-51° C. ¹HNMR (CDCl₃, 300 MHz) δ 3.91 (s, 2H), 7.68 (s, 2H), 7.84 (s, 1H), 9.86(s, 1H).

3-Methylthiophenylacetaldehyde: (1.9 g, 56%). ¹H NMR (CDCl₃, 300 MHz) δ2.48 (s, 3H), 3.66 (d, J=2.7 Hz, 2H), 6.96-7.03 (m, 1H) 7.07-7.23 (m,2H), 7.25-7.34 (m, 1H), 9.74 (s, 1H).

3-Trifluoromethylthiophenylacetaldehyde: (2.29 g, 80%). ¹H NMR (CDCl₃,300 MHz) δ 3.76 (d, J=2.4 Hz, 2H), 7.21-7.67 (m, 4H), 9.78 (s, 1H).

2-Methoxyphenylacetaldehyde: (2.04 g, 28%). ¹H NMR (CDCl₃, 300 MHz) δ3.33 (s, 2H), 3.83 (s, 3H), 6.87-7.02 (m, 2H) 7.12-7.37 (m, 2H), 9.69(s, 1H).

3-(3-Methyoxyphenyl)propionaldehyde: (2.4 g, 80%). ¹H NMR (CDCl₃, 300MHz) δ 2.78 (t, J=6.6 Hz, 2H), 2.94 (t, J=6.6 Hz, 2H), 3.80 (s, 3H),6.68-6.88 (m, 3H), 7.14-7.33 (m, 1H), 9.82 (s, 1H).

Example 14 Synthesis of Aldehyde Precursor to Compound II-4

4-Methoxy-3-trifluoromethylphenylacetaldehyde: (1.44 g, 67%). To acooled suspension of (methoxymethyl)triphenylphosphonium chloride (6.19g, 18 mmol) in THF (40 mL) was added dropwise a solution of sodiumbis(trimethylsilyl)amide in THF (1.0 M, 17.2 mL<17.2 mmol). Theresulting mixture was stirred at −78° C. for one hour, and then asolution of 4-methoxy-3-trifluoromethylbenzaldehyde (2.0 g, 9.8 mmol) inTHF (10 mL) was added. The resulting mixture was stirred at −78° C. for4 hours. The reaction was quenched with water. The layers wereseparated. The aqueous layer was extracted with ether (2×30 mL). Thecombined organic layers were washed with brine (20 mL), dried (MgSO₄),filtered, and concentrated in vacuo. The crude product was used in thenext step without any further purification. A solution of the crudeproduct from previous step was dissolved in a mixture of THF (40 mL) andHCl solution (3 N, 40 mL). The resulting mixture was stirred at roomtemperature overnight and then refluxed for 2 hours, cooled to roomtemperature. The layers were separated. The aqueous layer was extractedwith ether (2×20 mL). The combined organic layers were washed with brine(30 mL), filtered, and concentrated in vacuo. The residue was purifiedon flash column chromatography (silica gel, 5% EtOAc/hexane) to give anoil (0.74 g, 83%). ¹H NMR (CDCl₃, 300 MHz) δ 3.70 (s, 2H), 3.91 (s, 3H),7.02 (d, J=8.4 Hz, 1H) 7.31-7.47 (m, 2H), 9.75 (s, 1H).

Example 15 Synthesis of Aldehyde Precursor to Compound II-11

3-Dimethylaminophenylacetaldehyde: To a solution of3-dimethylaminobenzyl alcohol (4.6 g, 30 4 mmol) in acetone (250 mL) wasadded MnO₂ (26.4 g, 30.4 mmol). The resulting mixture was heated at 60°C. for 4 hours, cooled, and filtered through a short Celite pad. Thefiltrate was concentrated in vacuo. The residue was purified on flashcolumn chromatography (silica gel, 5% EtOAc/hexane) to give3-dimethylamino-benzaldehyde (3.1 g, 64%). ¹H NMR (CDCl₃, 300 MHz) δ3.02 (s, 6H), 6.94-7.04 (m, 1H), 7.16-7.25 (m, 2H), 7.34-7.46 (m, 1H),9.96 (s, 1H). To a cooled suspension of(methoxymethyl)triphenylphosphonium chloride (14.1 g, 41 mmol) in THF(40 mL) was added a solution of sodium bis (trimethylsilyl) amide in THF(1.0 M, 42.2 mL, 42.2 mmol). The resulting mixture was stirred at −78°C. for 1 hour, and then a solution of 3-dimethylaminobenzylaldehyde(3.06 g, 20.5 mmol) in THF (15 mL) was added. The resulting mixture wasstirred at −78° C. for 5 hours, and warmed gradually to room temperatureovernight. The reaction was quenched with water. The layers wereseparated. The aqueous layer was extracted with ether (2×40 mL). Thecombined organic layers were washed with brine (20 mL), dried (MgSO₄),filtered, and concentrated. The residue (3.63 g) was used directly inthe next step without any further purification. A solution of theresidue (3.63 g) and HCl (3.0 N, 70 mL) in THF (70 mL) was heated at 80°C. for 1 hour, and then cooled to room temperature. The layers wereseparated. The aqueous layer was extracted with EtOAc (3×30 mL). Thecombined organic layers were washed with brine, dried (MgSO4), filtered,and concentrated in vacuo. The residue was purified on flash columnchromatography (silica gel, 5% EtOAc/hexane) to give an oil (1.34 g,40%). ¹H NMR (CDCl₃, 300 MHz) δ 2.96 (s, 6H), 3.62 (d, J=3.0 Hz, 2H),6.50-6.74 (m, 3H) 7.19-7.26 (m, 1H), 9.74 (s, 1H).

Example 16 Wittig Reaction to Form Olefin Precursor to Formula II (E)-and (Z)-2-Fluoro-4-(3-fluoro-5-trifluoromethylphenyl)-E-but-2-enoic acidethyl ester

To a solution of 5.0 g (20.6 mmol) oftriethyl-2-fluoro-2-phosphonoacetate (Aldrich Chemical Co.) in 94 mL ofanhydrous THF cooled to 0° C. under Ar atmosphere in a 3 neck flaskaffixed with reflux condenser and addition funnel, was added 10.7 mL(21.4 mmol) of 2M isopropylmagnesium chloride solution in THF. Themixture was stirred for 20 min at 0° C., then at ambient temperature for35 min. The mixture was place in a 80° C. oil bath and brought toreflux, and a solution of 4.04 g (19.6 mmol) of3-Fluoro-5-trifluoromethyl-phenylacetaldehyde in 19.6 mL of anhydrousTHF was added over 5 min. Heating was continued for 30 minutes, and themixture was cooled to 0° C. and poured into 136 mL of saturated aqueousNH₄Cl and 45 mL of water. The mixture was extracted with two 100 mLportions of EtOAc. The combined EtOAc layers were washed with 100 mL ofwater and 50 mL of brine, dried (MgSO₄), filtered, and concentrated togive a brown oil. Purification by silica gel chromatography (2.5/97.5EtOAc/hexane) provided 2.75 g (46%) of (E)-isomer and 2.11 g (35%) of(Z)-isomer. E-isomer: ¹H NMR (CDCl₃, 300 MHz) δ 1.37 (t, J=7.3 Hz, 3H),3.96 (d, J=8.5 Hz, 2H), 4.35 (q, J=7.3 Hz, 2H), 6.03 (d of t, J=8.5,19.5 Hz, 1H) 7.09-7.29 (m, 3H). ¹³C NMR (CDCl₃, 75 MHz) δ 15.3, 32.5,63.2, 112.5 (d of q, J=3.7, 24.2 Hz), 120.2, 120.4, 120.8, 121.1, 122.4(m), 144.1 (d of d, J=2.4, 7.3 Hz), 149.5 (d, J=258 Hz), 162.1 (d, J=35Hz), 164.0 (d, J=249 Hz), MS (ESI) m/z calculated for C₁₃H₁₁F₅O₂ (M+1):295. Found: 231 (apparent loss of 64). Z-isomer: ¹H NMR (CDCl₃, 300 MHz)δ 1.31 (t, J=7.3 Hz, 3H), 3.61 (d, J=7.9 Hz, 2H), 4.28 (q, J=7.3 Hz,2H), 6.24 (d of t, J=7.9, 31.1 Hz, 1H) 7.08-7.26 (m, 3H). ¹³C NMR(CDCl₃, 75 MHz) δ 15.4, 31.3, 63.3, 112.6 (d of q, J=4.3, 24.4 Hz),117.9, 118.0, 120.2, 120.5, 122.4(m), 143.2 (d of d, J=2.4, 7.3 Hz),150.2 (d, J=260 Hz), 161.7 (d, J=35 Hz), 164.1 (d, J=249 Hz), MS (ESI)m/z calculated for C₁₃H₁₁F₅O₂ (M+1): 295. Found: 231 (apparent loss of64).

The compounds in the remainder of this example were synthesizedaccording to the procedure for (E)- and(Z)-2-Fluoro-4-(3-fluoro-5-trifluoromethylphenyl)-E-but-2-enoic acidethyl ester described above using the appropriate starting materialprepared from Example 13, 14, or 15.

(E)-Ethyl-2-fluoro-4-(3-trifluoromethylphenyl)-2-butenoate: (0.65 g,31%). ¹H NMR (CDCl₃, 300 MHz) δ 1.38 (t, J=7.2 Hz, 3H), 3.98 (d, J=8.7Hz, 2H), 4.36 (q, J=7.2 Hz, 2H), 6.05 (dt, J=20.1, 8.4 Hz, 1H),7.37-7.60 (m, 4H).

(E)-Ethyl-2-fluoro-4-(4-methoxyphenyl)-2-butenoate: (0.73 g, 35%). ¹HNMR (CDCl₃, 300MHz) δ 1.37 (t, J=7.2 Hz, 3H), 3.80 (s, 3H), 3.83 (d,J=7.8 Hz, 2H), 4.35 (q, J=7.2 Hz, 2H), 6.06 (dt, J=21.6, 7.8 Hz, 1H),6.85 (d, J=8.4 Hz, 2H), 7.14 (d, J=8.4 Hz, 2H).

(E)-Ethyl-2-fluoro-4-(4-methoxy-3-trifluoromethylphenyl)-2-butenoate:(0.54 g, 55%). ¹H NMR (CDCl₃, 300 MHz) δ 1.38 (t, J=7.2 Hz, 3H), 3.87(d, J=8.4 Hz, 2H), 3.88 (s, 3H), 4.35 (q, J=7.2 Hz, 2H), 6.02 (dt,J=20.1, 8.7 Hz, 1H), 6.95 (d, J=8.4 Hz, 1H), 7.30-7.48 (m, 2H).

(E)-Ethyl-2-fluoro-4-(4-fluorophenyl)-2-butenoate: (1.1 g, 58%). ¹H NMR(CDCl₃, 300 MHz) δ 1.37 (t, J=7.2 Hz, 3H), 3.87 (d, J=7.8 Hz, 2H), 4.35(q, J=7.2 Hz, 2H), 6.04 (dt, J=20.7, 8.7 Hz, 1H), 6.99 (d, J=8.7 Hz,2H), 7.14-7.23 (m, 2H).

(E)-Ethyl-2-fluoro-4-(3-methylphenyl)-2-butenoate: (0.4 g, 24%). ¹H NMR(CDCl₃, 300 MHz) δ 1.38 (t, J=7.2 Hz, 3H), 2.34 (s, 3H), 3.86 (d, J=8.4Hz, 2H), 4.35 (q, J=7.2 Hz, 2H), 6.08 (dt, J=21.3, 8.4 Hz, 1H),6.94-7.25 (m, 4H).

(E)-Ethyl-2-fluoro-4-(3-fluorophenyl)-2-butenoate: (1.1 g, 48%). ¹H NMR(CDCl₃, 300 MHz) δ 1.37 (t, J=7.2 Hz, 3H), 3.90 (d, J=8.1 Hz, 2H), 4.35(q, J=7.2 Hz, 2H), 6.05 (dt, J=21.0, 8.7 Hz, 1H), 6.87-7.07 (m, 3H),7.22-7.35 (m, 1H).

(E)-Ethyl-2-fluoro-4-(3-methoxyphenyl)-2-butenoate: (0.78 g, 37%). ¹HNMR (CDCl₃, 300 MHz) δ 1.37 (t, J=7.2 Hz, 3H), 3.80 (s, 3H), 3.87 (d,J=7.8 Hz, 2H), 4.34 (q, J=7.8 Hz, 2H), 6.08 (dt, J=20.7, 7.8 Hz, 1H),6.72-7.88 (m, 3H), 7.23 (t, J=7.8 Hz, 1H).

(E)-Ethyl-2-fluoro-4-phenyl-2-butenoate: (0.56 g, 28%). ¹H NMR (CDCl₃,300 MHz) δ 1.38 (t, J=7.2 Hz, 3H), 3.90 (d, J=8.7 Hz, 2H), 4.35 (q,J=7.2 Hz, 2H), 6.09 (dt, J=20.7, 8.7 Hz, 1H), 7.02-7.60 (m, 5H).

(E)-Ethyl-2-fluoro-4-(3-trifluoromethoxyphenyl)-2-butenoate: (1.5 g,72%). ¹H NMR (CDCl₃, 300 MHz) δ 1.37 (t, J=7.2 Hz, 3H), 3.92 (d, J=8.4Hz, 2H), 4.35 (q, J=6.6 Hz, 2H), 6.05 (dt, J=20.4, 8.4 Hz, 1H),7.04-7.21 (m, 3H), 7.34 (t, J=8.1 Hz, 1H).

(E)-Ethyl-2-fluoro-4-(3-dimethylaminophenyl)-2-butenoate: (0.39 g, 21%).¹H NMR (CDCl₃, 300 MHz) δ 1.38 (t, J=6.6Hz, 3H), 2.94 (s, 6H), 3.85 (d,J=8.1 Hz, 2H), 4.34 (q, J=6.6 Hz, 2H), 6.11 (dt, J=21.3, 8.1 Hz, 1H),6.53-6.70 (m, 3H), 7.18 (t, J=7.8 Hz, 1H).

(E)-Ethyl-2-fluoro-4-(3,5-ditrifluoromethylphenyl)-2-butenoate: (1.12 g,52%). ¹H NMR (CDCl₃, 300 MHz) δ 1.38 (t, J=7.2 Hz, 3H), 4.05 (d, J=8.4Hz, 2H), 4.36 (q, J=7.2 Hz, 2H), 6.05 (dt, J=19.8, 8.4 Hz, 1H), 7.68 (s,2H), 7.77 (s, 1H).

(E)-Ethyl-2-fluoro-4-(3-methylthiophenyl)-2-butenoate: (1.7 g, 59%). ¹HNMR (CDCl₃, 300 MHz) δ 1.35 (t, J=7.5 Hz, 3H), 2.48 (s, 3H), 3.87 (d,J=8.4 Hz, 2H), 4.35 (q, J=7.2 Hz, 2H), 6.06 (dt, J=20.7, 8.4 Hz, 1H),6.95-7.03 (m, 1H), 7.09-7.17 (m, 2H), 7.19-7.25 (m, 1H).

(E)-Ethyl-2-fluoro-4-(3-trifluoromethylthiophenyl)-2-butenoate: (1.88 g,61%). ¹H NMR (CDCl₃, 300 MHz) δ 1.38 (t, J=6.6 Hz, 3H), 3.93 (d, J=8.7Hz, 2H), 4.35 (q, J=7.2 Hz, 2H), 6.06 (dt, J=20.4, 8.4 Hz, 1H),7.31-7.43 (m, 2H), 7.47-760 (m, 2H).

(E)-Ethyl-2-fluoro-4-(2-methoxyphenyl)-2-butenoate: (0.92 g, 43%). ¹HNMR (CDCl₃, 300 MHz) δ 1.37 (t, J=7.2 Hz, 3H), 3.83 (s, 3H), 3.87 (d,J=8.4 Hz, 2H), 4.34 (q, J=7.2 Hz, 2H), 6.13 (dt, J=21.3, 7.8 Hz, 1H),6.81-6.96 (m, 2H), 7.14-7.29 (m, 2H).

(E)-Ethyl-2-fluoro-5-(3-methoxyphenyl)-2-pentenoate: (1.3 g, 45%). ¹HNMR (CDCl₃, 300 MHz) δ 1.34 (t, J=7.5 Hz, 3H), 2.69-2.91 (m, 4H), 3.80(s, 3H), 4.29 (q, J=7.2 Hz, 2H), 5.93 (dt, J=21.6, 7.2 Hz, 1H),6.70-6.87 (m, 3H), 7.16-7.26 (m, 1H).

(E)-Ethyl-2-fluoro-4-(3-methoxyphenyl)-4-methyl-2-butenoate: (0.6 g,27%). ¹H NMR (CDCl₃, 300 MHz) δ 1.35 (t, J=7.5 Hz, 3H), 1.78 (d, J=5.5Hz, 3H), 3.79 (s, 3H), 3.91 (s, 2H), 4.32 (q, J=7.5 Hz, 2H), 6.72-7.86(m, 3H), 7.16-7.26 (m, 1H).

Example 17 Synthesis of Alcohol Precursor to Formula II(E)-2-Fluoro-4-(3-fluoro-5-trifluoromethylphenyl)-but-2-en-1-ol

To a stirred solution of 1.77 g (6.02 mmol) of(E)-2-Fluoro-4-(3-fluoro-5-trifluoromethylphenyl)-E-but-2-enoic acidethyl ester in 30 mL of hexane under Ar atmosphere and cooled to between−30° C. and −15° C. was. added 12.04 mL (18.06 mmol) of a 1.SM solutionof diisobutylaluminum hydride in toluene over 2 min. The mixture wasstirred for 30 min with continued cooling, and 18 mL of MeOH was addedfollowed by 22.5 mL of 6N HCl solution. The mixture was extracted withtwo 50 mL portions of EtOAc, and the combined EtOAc layers were washedsequentially with water and brine, dried (MgSO₄), filtered, andconcentrated to an oil. Purification by silica gel chromatography (36/65EtOAc/hexane) provided 1.39 g (91%) of product as a colorless oil: ¹HNMR (CDCl₃, 300 MHz) δ 1.99 (brd t, J=5.5 Hz, 1H), 3.45 (d, J=8.5 Hz,2H), 4.33 (d of d, J=5.5, 10.8 Hz, 2H), 5.39 (d of t, J=8.5, 19.5 Hz,1H,) 7.09-7.25 (m, 3H).

The compounds in the remainder of this example were synthesizedaccording to the procedure for(E)-2-Fluoro-4-(3-fluoro-5-trifluoromethylphenyl)-but-2-en-1-oldescribed above using the appropriate starting material prepared fromExample 16.

(Z)-2-Fluoro-4-(3-fluoro-5-trifluoromethylphenyl)-but-2-en-1-ol: 94%yield: ¹H NMR (CDCl₃, 300 MHz) δ 1.99 (brd t, 1H), 3.51 (d, J=8.0 Hz,2H), 4.19 (d, J=14.6 Hz, 2H), 5.05 (d of t, J=7.9, 34.8 Hz, 1H)7.09-7.25 (m, 3H).

(E)-2-Fluoro-4-(3-trifluoromethylphenyl)-2-butenol: (0.52 g, 94%). ¹HNMR (CDCl₃, 300 MHz) δ 3.46 (d, J=7.8 Hz, 2H), 3.35 (d, J=20.1 Hz, 2H),5.56 (dt, J=20.1, 8.4 Hz, 1H), 7.35-7.59 (m, 4H),

(E)-2-Fluoro-4-(4-methoxyphenyl)-2-butenol: (0.41 g, 70%). ¹H NMR(CDCl₃, 300 MHz) δ 3.33 (d, J=8.4 Hz, 2H), 3.79 (s, 3H), 4.33 (d, J=20.7Hz, 2H), 5.45 (dt, J=20.7, 8.4 Hz, 1H), 6.85 (d, J=8.4 Hz, 2H), 7.11 (d,J=8.4 Hz, 2H),

(E)-2-Fluoro-4-(4-methoxy-3-trifluoromethylphenyl)-2-butenol: (0.39 g,83%). ¹H NMR (CDCl₃, 300 MHz) δ 3.36 (d, J=8.1 Hz, 2H), 3.89 (s, 3H),4.33 (d, J=21.3 Hz, 2H), 5.38 (dt, J=20.1, 8.1 Hz, 1H), 6.95 (d, J=8.4Hz, 1H), 7.29-7.43 (m, 2H),

(E)-2-Fluoro-4-(4-fluorophenyl)-2-butenol: (1.1 g, 90%). ¹H NMR (CDCl₃,300 MHz) δ 3.35 (d, J=8.7 Hz, 2H), 4.33 (dd, J=20.7, 6.0 Hz, 2H), 5.39(dt, J=21.0, 7.8 Hz, 1H), 6.99 (t, J=8.7 Hz, 2H), 7.09-7.21 (m, 2H),

(E)-2-Fluoro-4-(3-methylphenyl)-2-butenol: (0.24 g, 73%). ¹H NMR (CDCl₃,300 MHz) δ 2.34 (s, 3H), 3.35 (d, J=8.7 Hz, 2H), 4.33 (d, J=19.8 Hz,2H), 5.42 (dt, J=20.1, 8.4 Hz, 1H), 6.93-7.11 (m, 3H), 7.20 (t, J=8.1Hz, 1H).

(E)-2-Fluoro-4-(3-fluorophenyl)-2-butenol: (0.94 g, 87%). ¹H NMR (CDCl₃,300 MHz) δ 3.38 (d, J=7.8 Hz, 2H), 4.33 (d, J=21.3 Hz, 2H), 5.4o (dt,J=20.1, 8.7 Hz, 1H), 6.84-7.04 (m, 3H), 7.19-7.35 (m, 1H).

(E)-2-Fluoro-4-(3-methoxyphenyl)-2-butenol: (0.71 g, 93%). ¹H NMR(CDCl₃, 300 MHz) δ 3.36 (d, J=8.7 Hz, 2H), 3.80 (s, 3H), 4.33 (dd,J=20.7, 6.0 Hz, 2H), 5.42 (dt, J=20.7, 8.1 Hz, 1H), 6.68-6.87 (m, 3H),7.22 (t, J=7.8 Hz, 1H).

(E)-2-Fluoro-4-phenyl-2-butenol: (0.34 g, 93%). ¹H NMR (CDCl₃, 300 MHz)δ 3.39 (d, J=7.8 Hz, 2H), 4.34 (dd, J=20.7, 6.0 Hz, 2H), 5.43 (dt,J=20.7, 8.4 Hz, 1H), 7.13-7.39 (m, 5H).

(E)-2-Fluoro-4-(3-trifluoromethoxyphenyl)-2-butenol: (0.91 g, 83%). ¹HNMR (CDCl₃, 300 MHz) δ 3.42 (d, J=8.7 Hz, 2H), 4.33 (dd, J=20.7, 6.0 Hz,2H), 5.40 (dt, J=20.7, 8.4 Hz, 1H), 7.00-9.19 (m, 3H), 7.33 (t, J=8.1Hz, 1H).

(E)-2-Fluoro-4-(3-dimethylaminophenyl)-2-butenol: (0.2 g, 60%). ¹H NMR(CDCl₃, 300 MHz) δ 2.94 (s, 6H), 3.34 (d, J=8.4 Hz, 2H), 4.33 (dd,J=21.3, 3.6 Hz, 2H), 5.45 (dt, J=20.1, 8.4 Hz, 1H), 6.50-6,71 (m, 3H),7.18 (t, J=7.8 Hz, 1H),

(E)-2-Fluoro-4-(3,5-ditrifluoromethylphenyl)-2-butenol: (0.61 g, 64%).¹H NMR (CDCl₃, 300 MHz) δ 3.55 (d, J=8.1 Hz, 2H), 4.37 (dd, J=20.1, 6.3Hz, 2H), 5.41 (dt, J=19.5, 7.8 Hz, 1H), 7.66 (s, 2H), 7.75 (s, 1H).

(E)-2-Fluoro-4-(3-methylthiophenyl)-2-butenol: (1.1 g, 78%). ¹H NMR(CDCl₃, 300 MHz) δ 2.48 (s, 3H), 3.35 (d, J=8.1 Hz, 2H), 3.80 (s, 3H),4.33 (dd, J=20.1, 3.0 Hz, 2H), 5.41 (dt, J=20.1, 8.4 Hz, 1H), 6.96 (d,J=7.2 Hz, 1H), 7.05-7.17 (m, 2H), 7.23 (t, J=8.1 Hz, 1H).

(E)-2-Fluoro-4-(3-trifluoromethylthiophenyl)-2-butenol: (1.3 g, 78%). ¹HNMR (CDCl₃, 300 MHz) δ 3.42 (d, J=8.1 Hz, 2H), 4.35 (d, J=21.3 Hz, 2H),5.41 (dt, J=20.1, 7.8 Hz, 1H), 7.29-7.42 (m, 2H), 7.45-7.60 (m, 2H).

(E)-2-Fluoro-4-(2-methoxyphenyl)-2-butenol: (0.65 g, 89%). ¹H NMR(CDCl₃, 300 MHz) δ 3.36 (d, J=8.4 Hz, 2H), 3.84 (s, 3H), 4.35 (dd,J=21.6, 6.9 Hz, 2H), 5.37 (dt, J=20.1, 8.7 Hz, 1H), 6.80-6.99 (m, 2H),7.09-7.33 (m, 2H),

(E)-2-Fluoro-5-(3-methoxyphenyl)-2-pentenol: (0.95 g, 90%). ¹H NMR(CDCl₃, 300 MHz) δ 2.33 (q, J=7.2 Hz, 2H), 2.67 (t, J=7.2 Hz, 2H), 3.80(s, 3H), 4.03 (d, J=21.3 Hz, 2H), 5.22 (dt, J=20.7, 8.4 Hz, 1H),6.68-6.87 (m, 3H), 7.22 (t, J=8.1 Hz, 1H).

(E)-2-Fluoro-4-(3-methoxyphenyl)-4-methyl-2-butenol: (0.26 g, 55%). ¹HNMR (CDCl₃, 300 MHz) δ 1.63 (d, J=3.9 Hz, 3H), 3.34 (s, 2H), 3.80 (s,3H), 4.38 (dd, J=22.5, 6.0 Hz, 2H), 6.69-6.83 (m, 3H), 7.22 (t, J=7.8Hz, 1H).

Example 18 Synthesis of N-phthalyl-protected Precursors to Formula II(E)-N-(2-Fluoro-4-(3-fluoro-5-trifluoromethylphenyl)-but-2-enyl)phthalimide

To a stirred partially dissolved solution of 849 mg (3.37 mmol) of(E)-2-Fluoro-4-(3-fluoro-5-trifluoromethylphenyl)-but-2-en-1-ol, 546 mg(3.71 mmol) of phthalimide, and 1.326 g (5.05 mmol) oftriphenylphosphine in 16.35 mL of THF at 0° C. was added over 8 min asolution of 1.021 g (5.05 mmol) of diisopropylazodicarboxylate in 8 mLof THF. The cooling bath was removed, and the mixture was stirred atambient temperature for 18 h. THF was removed under vacuum, and theresidue was purified by silica gel chromatography (15/85 EtOAc/hexane)to provide 1.05 g (82%) of product as a white solid: ¹H NMR (CDCl₃, 300MHz) δ 3.66 (d, J=8.5 Hz, 2H), 4.54 (d, J=19.5 Hz, 2H), 5.44 (d of t,J=7.9, 19.5 Hz, 1H,) 7.17-7.33 (m, 3H), 7.75 (m, 2H), 7.88 (m, 2H).

The compounds in the remainder of this example were synthesizedaccording to the procedure for(E)-N-(2-Fluoro-4-(3-fluoro-5-trifluoromethylphenyl)-but-2-enyl)phthalimidedescribed above using the appropriate starting material prepared fromExample 17.

(Z)-N-(2-Fluoro-4-(3-fluoro-5-trifluoromethylphenyl)-but-2-enyl)phthalimide:93% yield: ¹H NMR (CDCl₃, 300 MHz) δ 3.48 (d, J=13.4 Hz, 2H), 4.44 (d,J=7.9 Hz, 2H), 5.11 (d of t, J=7.9, 34.2 Hz, 1H) 7.07-7.23 (m, 3H), 7.75(m, 2H), 7.89 (m, 2H).

(E)-N-(2-Fluoro-4-(3-trifluoromethylphenyl)-2-butenyl)phthalimide: (0.68g, 86%). Mp: 75-76° C. ¹H NMR (CDCl₃, 300 MHz) δ 3.67 (d, J=8.7 Hz, 2H),4.46 (d, J=19.5 Hz, 2H), 5.46 (dt, J=19.5, 8.1 Hz, 1H), 7.35-7.59 (m,4H), 7.71-7.81 (m, 2H), 7.83-7.98 (m, 2H)

(E)-N-(2-Fluoro-4-(4-methoxyphenyl)-2-butenyl)phthalimide: (0.57 g,85%). Mp: 43-44° C. ¹H NMR (CDCl₃, 300 MHz) δ 3.54 (d, J=8.1 Hz, 2H),3.80 (s, 3H), 4.55 (d, J=18.9 Hz, 2H), 5.44 (dt, J=21, 8.7 Hz, 1H), 6.86(d, J=8.4 Hz, 2H), 7.19 (d, J=8.4 Hz, 2H), 7.71-7.81 (m, 2H), 7.83-7.98(m, 2H).

(E)-N-(2-Fluoro-4-(4-methoxy-3-trifluoromethylphenyl)-2-butenyl)phthalimide:(0.54 g, 94%). Mp: 107-109° C. ¹H NMR (CDCl₃, 300 MHz) δ 3.57 (d, J=7.2Hz, 2H), 3.89 (s, 3H), 4.55 (d, J=18.9 Hz, 2H), 5.42 (dt, J=19.5, 8.7Hz, 1H), 6.96 (d, J=7.8 Hz, 1H), 7.36-7.50 (m, 2H), 7.71-7.83 (m, 2H),7.84-7.98 (m, 2H).

(E)-N-(2-Fluoro-4-(4-fluorophenyl)-2-butenyl)phthalimide: (0.91 g, 78%).Mp: 80-81° C. ¹H NMR (CDCl₃, 300 MHz) δ 3.57 (d, J=7.8 Hz, 2H), 4.55 (d,J=19.5 Hz, 2H), 5.43 (dt, J=19.5, 8.1 Hz, 1H), 7.00 (t, J=8.7 Hz, 2H),7.18-7.36 (m, 2H), 7.71-7.81 (m, 2H), 7.83-7.98 (m, 2H).

(E)-N-(2-Fluoro-4-(3-methylphenyl)-2-butenyl)phthalimide: (0.33 g, 84%).Mp: 75-76° C. ¹H NMR (CDCl₃, 300 MHz) δ 2.34 (s, 3H), 3.56 (d, J=8.1 Hz,2H), 4.55 (d, J=18.9 Hz, 2H), 5.47 (dt, J=19.5, 8.4 Hz, 1H), 6.96-7.14(m, 3H), 7.21 (t, J=8.4 Hz, 1H), 7.67-7.82 (m, 2H), 7.83-7.98 (m, 2H).

(E)-N-(2-Fluoro-4-(3-fluorophenyl)-2-butenyl)phthalimide: (0.93 g, 85%).Mp: 62-63° C. ¹H NMR (CDCl₃, 300 MHz) δ 3.60 (d, J=8.1 Hz, 2H), 4.54 (d,J=19.8 Hz, 2H), 5.45 (dt, J=19.8, 8.1 Hz, 1H), 6.84-7.14 (m, 3H),7.18-7.40 (m, 1H), 7.67-7.82 (m, 2H), 7.83-7.98 (m, 2H)

(E)-N-(2-Fluoro-4-(3-methoxyphenyl)-2-butenyl)phthalimide: (0.9 g, 84%).Mp: 74-75° C. ¹H NMR (CDCl₃, 300 MHz) δ 3.57 (d, J=7.8 Hz, 2H), 3.82 (s,3H), 4.55 (d, J=18.9 Hz, 2H), 5.47 (dt, J=20.1, 7.8 Hz, 1H), 6.68-6.95(m, 3H), 7.23 (t, J=8.1 Hz, 1H), 7.67-7.82 (m, 2H), 7.83-7.98 (m, 2H)

(E)-N-(2-Fluoro-4-phenyl-2-butenyl)phthalimide: (0.5 g, 84%). Mp: 73-74°C. ¹H NMR (CDCl₃, 300 MHz) δ 3.60 (d, J=8.7 Hz, 2H), 4.56 (d, J=18.9 Hz,2H), 5.48 (dt, J=19.5, 8.4 Hz, 1H), 7.15-7.42 (m, SH), 7.67-7.82 (m,2H), 7.83-7.98 (m, 2H).

(E)-N-(2-Fluoro-4-(3-trifluoromethoxyphenyl)-2-butenyl)phthalimide: (1.1g, 84%). ¹H NMR (CDCl₃, 300 MHz) δ 3.63 (d, J=8.4 Hz, 2H), 4.55 (d,J=19.5 Hz, 2H), 5.46 (dt, J=19.8, 7.8 Hz, 1H), 7.03-7.26 (m, 3H), 7.34(t, J=8.7 Hz, 1H), 7.67-7.82 (m, 2H), 7.83-7.98 (m, 2H)

(E)-N-(2-Fluoro-4-(3-dimethylaminophenyl)-2-butenyl)phthalimide: (0.23g, 75%). Mp: 96-97° C. ¹H NMR (CDCl₃, 300 MHz) δ 2.95 (s, 6H), 3.55 (d,J=7.2 Hz, 2H), 4.56 (d, J=19.5 Hz, 2H), 5.49 (dt, J=20.1, 8.7 Hz, 1H),6.50-6.76 (m, 3H), 7.18 (t, J=7.2 Hz, 2H), 7.69-7.81 (m, 2H), 7.83-7.95(m, 2H).

(E)-N-(2-Fluoro-4-(3,5-ditrifluoromethylphenyl)-2-butenyl)phthalimide:(0.84 g, 71%). Mp: 112-113° C. ¹H NMR (CDCl₃, 300 MHz) δ 3.75 (d, J=7.8Hz, 2H), 4.56 (d, J=20.1 Hz, 2H), 5.44 (dt, J=19.5, 8.1 Hz, 1H),7.71-7.83 (m, 5H), 7.84-7.96 (m, 2H).

(E)-N-(2-Fluoro-4-(3-methylthiophenyl)-2-butenyl)phthalimide: (1.33 g,75%). Mp: 88-89° C. ¹H NMR (CDCl₃, 300 MHz) δ 2.50 (s, 3H), 3.57 (d,J=7.8 Hz, 2H), 4.55 (d, J=19.8 Hz, 2H), 5.45 (dt, J=20.4, 7.8 Hz, 1H),7.00-7.32 (m, 4H), 7.69-7.80 (m, 2H), 7.83-7.95 (m, 2H).

(E)-N-(2-Fluoro-4-(3-trifluoromethylthiophenyl)-2-butenyl)phthalimide:(1.61 g, 90%). Mp: 54-55° C. ¹H NMR (CDCl₃, 300 MHz) δ 3.64 (d, J=7.8Hz, 2H), 4.55 (d, J=20.1 Hz, 2H), 5.45 (dt, J=19.5, 7.8 Hz, 1H),7.31-7.46 (m, 2H), 7.48-7.60 (m, 2H), 7.70-7.81 (m, 2H), 7.84-7.95 (m,2H).

(E)-N-(2-Fluoro-4-(2-methoxyphenyl)-2-butenyl)phthalimide: (0.79 g,75%). Mp: 88-89° C. ¹H NMR (CDCl₃, 300 MHz) δ 3.55 (d, J=8.1 Hz, 2H),3.85 (s, 3H), 4.60 (d, J=19.8 Hz, 2H), 5.46 (dt, J=20.1, 8.7 Hz, 1H),6.78-7.01 (m, 2H), 7.16-7.33 (m, 2H), 7.69-7.81 (m, 2H), 7.83-7.95 (m,2H).

(E)-N-(2-Fluoro-5-(3-methoxyphenyl)-2-pentenyl)phthalimide: (1.14 g,75%). Mp: 86-87° C. ¹H NMR (CDCl₃, 300 MHz) δ 2.54 (q, J =8.1 Hz, 2H),2.74 (d, J=8.1 Hz, 2H), 3.82 (s, 3H), 4.33 (d, J=20.1 Hz, 2H), 5.29 (dt,J=20.7, 7.8 Hz, 1H), 6.67-6.91 (m, 3H), 7.22 (t, J=8.1 Hz, 1H),7.67-7.80 (m, 2H), 7.81-7.96 (m, 2H).

(E)-N-(2-Fluoro-4-(3-methoxyphenyl)-4-methyl-2-butenyl)phthalimide:(0.56 g, 65%). Mp: 99-100° C. ¹H NMR (CDCl₃, 300 MHz) δ 1.60 (d, J=3.6hz, 3H), 3.57 (s, 2H), 3.82 (s, 3H), 4.61 (d, J=20.1 Hz, 2H), 6.71-6.89(m, 2H), 7.17-7.32 (m, 2H), 7.71-7.81 (m, 2H), 7.83-7.98 (m, 2H).

Example 19 Synthesis of N-phthalyl-protected Precursor to CompoundII-14-E

(E)-N-(2-Fluoro-4-(3- methanesulfonylphenyl)-2-butenyl)phthalimide: Asolution of periodic acid (0.2 g, 0.87 mmol) in dry acetonitrile (2.5mL) was stirred vigorously for one hour, and then CrO₃ (4.16 mg, 0.042mmol) was added. The resulting mixture was stirred at room temperaturefor 5 min to give a clear orange solution. This periodic acid/CrO₃complex solution was added dropwise over a period of 45 min to asolution of (E)-2-Fluoro-4-(3-methylthiophenyl)-2-butenolphthalimide(0.142 g, 0.42 mmol) in EtOAc (5.0 mL) at −35° C. The resulting mixturewas stirred at −35° C. for one hour, and quenched by the addition ofsaturated Na₂SO₃ solution (10 mL). The mixture was filtered, and thesolid was washed EtOAc. The filtrate was washed with saturated Na₂SO₃solution (2×20 mL) and brine (20 mL), dried (MgSO₄), filtered, andconcentrated in vacuo to give a solid (0.13 g, 83%). Mp: 124-126° C. ¹HNMR (CDCl₃, 300 MHz) δ 3.10 (s, 3H), 3.70 (d, J=8.4 Hz, 2H), 4.57 (d,J=19.8 Hz, 2H), 5.46 (dt, J=19.5, 8.7 Hz, 1H), 7.48-7.66 (m, 3H),7.72-7.80 (m, 2H), 7.81-7.86 (m, 1H), 7.86-7.98 (m, 2H)

Example 20 N-phthalyl Deprotection to Form Compounds of Formula II(E)-2-Fluoro-4-(3-fluoro-5-trifluoromethylphenyl)-but-2-enylamine(II-1-E)

(E)-N-(2-Fluoro-4-(3-fluoro-5-trifluoromethylphenyl)-but-2-enyl)phthalimide(844 mg, 2.21 mmol) was dissolved in a mixture of 18.4 mL of EtOH and36.7 mL of a 33% solution of MeNH₂ in EtOH. The resulting solution wasrefluxed under Ar atmosphere for 2.5 h. When cool the mixture wasconcentrated under vacuum, and the residue was purified by silica gelchromatography (50/50/0.1 CH₃CN/CH₂Cl₂/conc. NH₄OH) to provide 492 mg(89%) of desired product as an oil: ¹H NMR (CDCl₃) δ 3.45 (d, J=8.0 Hz,2H), 3.50 (d, J=20.8 Hz, 2H), 5.25 (d of t, J=7.9, 20.1 Hz, 1H)7.07-7.23 (m, 3H).

(Z)-2-Fluoro-4-(3-fluoro-5-trifluoromethylphenyl)-but-2-enylamine(II-1-Z): This compound was prepared from(Z)-N-(2-Fluoro-4-(3-fluoro-5-trifluoromethylphenyl)-but-2-enyl)phthalimideas described above for II-1-E. 90% yield: ¹H NMR (CDCl₃, 300 MHz) δ 3.39(d, J=13.4 Hz, 2H), 3.47 (d, J=7.9 Hz, 2H), 4.90 (d of t, J=7.9, 35.4Hz, 1H) 7.24-7.08 (m, 3H).

Example 21 HCl Salt Formation for Compounds of Formula II(E)-2-Fluoro-4-(3-fluoro-5-trifluoromethylphenyl)-but-2-enylamine HClSalt (II-1-E)

To a solution of 473 mg (1.88 mmol) of the free amine, compound II-1-E,in 9.4 mL of anhydrous Et₂O was added 3.76 mL (3.76 mmol) of a 1Msolution of HCl in Et₂O. The resulting white precipitate was collectedby filtration to provide 419 mg (77%) of hydrogen chloride salt as awhite solid: m.p. 179-180° C.; Elemental analysis calculated forC₁₁H₁₁ClF₅N: C, 45.93; H, 3.85; N, 4.87. Found: C, 46.17; H, 3.89; N,5.00.

(Z)-2-Fluoro-4-(3-fluoro-5-trifluoromethylphenyl)-but-2-enylamine HClsalt (II-1-Z): This compound was prepared from compound II-1-Z asdescribed above for II-1-E. 88% yield: m.p. 89.5-91.5° C.; Elementalanalysis calculated for C₁₁H₁₁ClF₅N: C, 45.93; H, 3.85; N, 4.87. Found:C, 45.76; H, 3.79; N, 5.05.

Example 22 Sequential N-phthalyl Deprotection and HCl Salt Formation forCompounds of Formula II

The salt form of compounds of formula II described in this example wereprepared in a sequential fashion by performing the deprotectiondescribed in Example 20 followed by the HCl salt formation described inExample 21.

(E)-2-Fluoro-4-(3-trifluoromethylphenyl)-2-butenylamine hydrochloride(II-2): (0.21 g, 93%). Mp: 145-147° C. ¹H NMR (MeOD-d₃, 300 MHz) δ 3.57(d, J=7.8 Hz, 2H), 4.00 (d, J=19.5 Hz, 2H), 5.69 (dt, J=20.1, 7.8 Hz,1H), 7.38-7.76 (m, 4H). ESMS m/z 234 (M+H)⁺. Calcd for C₁₁H₁₂ClF₄N: C;48.99, H; 4.48, N; 5.19. Found: C; 49.17, H; 3.96, N; 5.27.

(E)-2-Fluoro-4-(4-methoxyphenyl)-2-butenylamine hydrochloride (II-3):(0.32 g, 86%). Mp: 232-233° C. ¹H NMR (MeOD-d₃, 300 MHz) δ 3.44 (d,J=8.7 Hz, 2H), 3.87 (s, 3H), 3.96 (d, J=18.9 Hz, 2H), 5.67 (dt, J=21.0,7.8 Hz, 1H), 7.12 (d, J=7.8 Hz, 1H), 7.39-7.56 (m, 2H). ESMS m/z 264(M+H)⁺. Calcd for C₁₂H₁₄ClF₄NO: C; 48.09, H; 4.71, N; 4.67. Found: C;47.93, H; 4.27, N; 4.83.

(E)-2-Fluoro-4-(4-methoxy-3-trifluoromethylphenyl)-2-butenylaminehydrochloride (II-4): (0.3 g, 74%). Mp: 146-147° C. ¹H NMR (MeOD-d₃, 300MHz) δ 3.36 (d, J=7.8 Hz, 2H), 3.75 (s, 3H), 3.92 (d, J=19.5 Hz, 2H),5.65 (dt, J=20.7, 8.1 Hz, 1H), 6.86 (d, J=8.4 Hz, 2H), 7.13 (d, J=8.4Hz, 2H). ESMS m/z 196 (M+H)⁺. Calcd for C₁₁H₁₅ClFNO: C; 57.02, H; 6.52,N; 6.04. Found: C; 56.88, H; 6.04, N; 6.37.

(E)-2-Fluoro-4-(4-fluorophenyl)-2-butenylamine hydrochloride (II-5):(0.51 g, 82%). Mp: 213-214° C. ¹H NMR (MeOD-d₃, 300 MHz) δ 3.42 (d,J=8.4 Hz, 2H), 3.95 (d, J=19.5 Hz, 2H), 5.66 (dt, J=21, 8.1 Hz, 1H),7.02 (t, J=8.7 Hz, 2H), 7.18-7.33 (m, 2H). ESMS m/z 184 (M+H)⁺. Calcdfor C₁₀H₁₂ClF₂N: C; 54.68, H; 5.51, N; 6.38. Found: C; 54.51, H; 5.59,N; 6.36.

(E)-2-Fluoro-4-(3-methylphenyl)-2-butenylamine hydrochloride (II-6):(0.16 g, 97%). Mp: 195-196° C. ¹H NMR (MeOD-d₃, 300 MHz) δ 2.31 (s, 3H),3.39 (d, J=8.7 Hz, 2H), 3.94 (d, J=19.5 Hz, 2H), 5.66 (dt, J=21.0, 8.4Hz, 1H), 6.69-7.10 (m, 3H), 7.17 (t, J=7.2 Hz, 1H). ESMS m/z 180 (M+H)⁺.Calcd for C₁₁H₁₅ClFN: C; 61.25, H; 7.01, N; 6.49. Found: C; 61.28, H;6.78, N; 6.56.

(E)-2-Fluoro-4-(3-fluorophenyl)-2-butenylamine hydrochloride (II-7):(0.12 g, 78%). Mp: 175-176° C. ¹H NMR (MeOD-d₃, 300 MHz) δ 3.46 (d,J=8.7 Hz, 2H), 3.95 (d, J=19.5 Hz, 2H), 5.68 (dt, J=20.1, 8.4 Hz, 1H),6.89-7.12 (m, 3H), 7.24-7.41 (m, 1H). ESMS m/z 184 (M+H)⁺. Calcd forC₁₀H₁₂ClF₂N: C; 54.68, H; 5.51, N; 6.38. Found: C; 54.73, H; 5.15, N;6.66.

(E)-2-Fluoro-4-(3-methoxyphenyl)-2-butenylamine hydrochloride (II-8):(0.47 g, 75%). Mp: 175-176° C. ¹H NMR (MeOD-d₃, 300 MHz) δ 3.40 (d,J=8.7 Hz, 2H), 3.77 (s, 3H), 3.94 (d, J=18.9 Hz, 2H), 5.68 (dt, J=20.7,7.8 Hz, 1H), 6.72-6.87 (m, 3H), 7.15-7.28 (m, 1H). ESMS m/z 196 (M+H)⁺.Calcd for C₁₁H₁₅ClFNO: C; 57.02, H; 6.52, N; 6.04. Found: C; 57.10, H;6.13, N; 6.25.

(E)-2-Fluoro-4-phenyl-2-butenylamine hydrochloride (II-9): (0.11 g,95%). Mp: 120-121° C. ¹H NMR (MeOD-d₃, 300 MHz) δ 3.44 (d, J=8.4 Hz,2H), 3.95 (d, J=19.5 Hz, 2H), 5.68 (dt, J=20.7, 7.8 Hz, 1H), 7.17-7.39(m, 5H). ESMS m/z 166 (M+H)⁺. Calcd for C₁₀H₁₃ClFN: C; 59.56, H; 6.50,N; 6.95. Found: C; 59.77, H; 6.30, N; 7.16.

(E)-2-Fluoro-4-(3-trifluoromethoxyphenyl)-2-butenylamine hydrochloride(II-10): (0.75g, 98%). Mp: 174-175° C. ¹H NMR (MeOD-d₃, 300 MHz) δ 3.50(d, J=8.7 Hz, 2H), 3.96 (d, J=19.5 Hz, 2H), 5.69 (dt, J=20.7, 8.1 Hz,1H), 7.11-7.31 (m, 3H), 7.41 (t, J=7.2 Hz, 1H). ESMS m/z 250 (M+H)⁺.Calcd for C₁₁H₁₂ClF₄NO: C; 46.25, H; 4.23, N; 4.90. Found: C; 46.26, H;4.39, N; 4.94.

(E)-2-Fluoro-4-(3-dimethylaminophenyl)-2-butenylamine hydrochloride(II-11): (0.16 g, 85%). ¹H NMR (MeOD-d₃, 300 MHz) δ 13.27 (s, 6H), 3.55(d, J=7.8 Hz, 2H), 4.00 (d, J=19.5 Hz, 2H), 5.71 (dt, J=20.1, 8.7 Hz,1H), 7.37-7.61 (m, 4H). ESMS m/z 209 (M+H)⁺.

(E)-2-Fluoro-4-(3,5-ditrifluoromethylphenyl)-2-butenylaminehydrochloride (II-12): (0.51 g, 79%). Mp: 197-198° C. ¹H NMR (MeOD-d₃,300 MHz) δ 3.65 (d, J=7.8 Hz, 2H), 4.00 (d, J=19.5 Hz, 2H), 5.74 (dt,J=20.1, 7.8 Hz, 1H), 7.85 (s, 1H), 7.88 (s, 2H). ESMS m/z 302 (M+H)⁺.Calcd for C₁₂H₁₁ClF₇N: C; 42.68, H; 3.28, N; 4.15. Found: C; 42.89, H;3.49, N; 4.51.

(E)-2-Fluoro-4-(3-methylthiophenyl)-2-butenylamine hydrochloride(II-13): (0.13 g, 96%). Mp: 192-193° C. ¹H NMR (MeOD-d₃, 300 MHz) δ 2.46(s, 3H), 3.41 (d, J=7.8 Hz, 2H), 3.94 (d, J=18.9 Hz, 2H), 5.67 (dt,J=20.7, 7.8 Hz, 1H), 7.00 (d, J=7.8 Hz, 1H), 7.08-7.18 (m, 2H), 7.24 (t,J=7.8 Hz, 1H). ESMS m/z 212 (M+H)⁺. Calcd for C₁₁H₁₅ClFNS: C; 53.32, H;6.10, N; 5.65. Found: C; 53.13, H; 5.77, N; 5.72.

(E)-2-Fluoro-4-(3-methanesulfonylphenyl)-2-butenylamine hydrochloride(II-14): (0.33 g, 66%). Mp: 196-197° C. ¹H NMR (MeOD-d₃, 300 MHz) δ 3.12(s, 3H), 3.58 (d, J=8.7 Hz, 2H), 3.99 (d, J=19.5 Hz, 2H), 5.72 (dt,J=20.1, 8.1 Hz, 1H), 7.54-7.70 (m, 2H), 7.78-7.98 (m, 2H). ESMS m/z 244(M+H)⁺. Calcd for C₁₁H₁₅ClFNO₂S: C; 47.23, H; 5.40, N; 5.01. Found: C;46.92, H; 5.68, N; 5.15.

(E)-2-Fluoro-4-(3-trifluoromethylthiophenyl)-2-butenylaminehydrochloride (II-15): (0.26 g, 72%). Mp: 188-189° C. ¹H NMR (MeOD-d₃,300 MHz) δ 3.51 (d, J=8.1 Hz, 2H), 3.97 (d, J=19.5 Hz, 2H), 5.69 (dt,J=20.1, 8.7 Hz, 1H), 7.42-7.52 (m, 2H), 7.54-7.70 (m, 2H). ESMS m/z 266(M+H)⁺. Calcd for C₁₁H₁₂ClF₄NS: C; 43.79, H; 4.01, N; 4.64. Found: C;43.64, H; 4.31, N; 4.81.

(E)-2-Fluoro-4-(2-methoxyphenyl)-2-butenylamine hydrochloride (II-17):(0.46 g, 83%). Mp: 133-134° C. ¹H NMR (MeOD-d₃, 300 MHz) δ 3.36 (d,J=8.4 Hz, 2H), 3.84 (s, 3H), 3.97 (d, J=19.5 Hz, 2H), 5.61 (dt, J=20.7,8.4 Hz, 1H), 6.83-7.03 (m, 2H), 7.09-7.34 (m, 2H). ESMS m/z 196 (M+H)⁺.Calcd for C₁₁H₁₅ClFNO: C; 57.02, H; 6.52, N; 6.04. Found: C; 57.38, H;6.78, N; 6.19.

(E)-2-Fluoro-4-(3-methoxyphenyl)-4-methyl-2-butenylamine hydrochloride(II-18): (0.27 g, 78%). Mp: 133-134° C. ¹H NMR (MeOD-d₃, 300 MHz) δ 1.65(d, J=3.9 Hz, 3H), 3.40 (s, 2H), 3.77 (s, 3H), 3.98 (d, J=20.1 Hz, 2H),6.69-7.84 (m, 2H), 7.22 (t, J=8.7 Hz, 1H). ESMS m/z 210 (M+H)⁺. Calcdfor C₁₂H₁₇ClFNO: C; 58.66, H; 6.97, N; 5.70. Found: C; 58.38, H; 6.79,N; 6.03.

(E)-2-Fluoro-5-(3-methoxyphenyl)-2-pentenylamine hydrochloride (II-24):(0.69 g, 86%). Mp: 112-113° C. ¹H NMR (MeOD-d₃, 300 MHz) δ 2.38 (q,J=21.3, 8.1 Hz, 1H), 6.72-6.86 (m, 3H), 7.14-7.28 (m, 1H). ESMS m/z 210(M+H)⁺. Calcd for C₁₂H₁₇ClFNO: C; 58.66, H; 6.97, N; 5.70. Found: C;58.75, H; 7.26, N; 5.96.

Example 23 Synthesis of Compound II-16

(E)-N-t-Butoxycarbonyl-2-fluoro-4-bromo-butenylamine: To a cooledsolution of (E)-N-t-butoxycarbonyl-2-fluoro-4-hydroxyl-butenylamine(0.396 g, 1.93 mmol, see synthesis below) and CBr₄ (0.96 g, 2.89 mmol)in dichloromethane (15 mL) was added a solution of PPh₃ (0.76 g, 2.89mmol) in dichloromethane (5 mL). The resulting mixture was stirred atroom temperature overnight, and then concentrated in vacuo. The residuewas purified on flash column chromatography (silica gel, 10%EtOAc/hexane) to give the desired product as a solid (0.36 g, 69%). Mp:39-40° C. ¹H NMR (CDCl₃, 300 MHz) δ 1.45 (s, 9H), 3.98 (dd, J=20.7, 6.0Hz, 2H), 4.09 (d, J=8.7 Hz, 2H), 5.54 (dt, J=17.1, 8.4 Hz, 1H).

(E)-N-t-Butoxycarbonyl-2-fluoro-4-(3-methoxymethylphenyl)-2-butenylamine:A mixture of 3-(methoxymethyl)phenylboronic acid (0.275 g, 1.66 mmol),(E)-N-t-Butoxycarbonyl-2-fluoro-4-bromo-2-butenylamine (0.0.21 g, 0.78mmol), K2CO3 (0.95 g, 6.85 mmol), and bis(dibenzylideneacetone)palladium(0) (8.88 mg, 0.015 mmol) in benzene (10 mL) was heated under N₂ at 85°C. for 20 min, cooled to room temperature. EtOAc (20 mL) and brine (10mL) were added. The layers were separated. The aqueous layer wasextracted with EtOAc (2×10 mL). The combined organic layers were washedwith brine (10 mL), dried (Na₂SO₄), filtered, and concentrated. Theresidue was purified on flash column chromatography (silica gel, 2%EtOAc/hexane) to give the desired product (0.17 g, 65%). ¹H NMR (CDCl₃,300 MHz) δ 1.46 (s, 9H), 3.37-3.46 (m, 5H), 3.94-4.08 (m, 2H), 5.27-5.46(m, 2H), 6.02-6.20 (m, 1H), 7.08-7.43 (m, 4H).

(E)-2-Fluoro-4-(3-methoxymethylphenyl)-2-butenylamine hydrochloride(II-16): This deprotection was carried out as described in Example 8.(0.13 g, 96%). Mp: 165-166° C. ¹H NMR (MeOD-d₃, 300 MHz) δ 3.37 (s, 3H),3.58 (d, J=8.4 Hz, 2H), 3.96 (d, J=18.9 Hz, 2H), 4.44 (s, 2H), 5.69 (dt,J=20.7, 8.7 Hz, 1H), 7.13-7.25 (m, 3H), 7.30 (t, J=7.2 Hz, 1H). ESMS m/z210 (M+H)⁺. Calcd for C₁₂H₁₇ClFNO: C; 58.66, H; 6.97, N; 5.70. Found: C;58.43, H; 6.66, N; 5.70.

Example 24 Synthesis of Scheme 5 Intermediates Ethyl(tert-butyldiphenylsilanyloxy)acetate

To a cooled solution of ethyl glycolate (5.31 g, 50 mmol) and imidazole(4.17 g, 61 mmol) in DMF (90 mL) was added tert-butyldiphenyl silanechloride (15.7 mL, 61.2 mmol). The reaction mixture was stirred at roomtemperature for 4 hours, concentrated in vacuo to give crude product.This crude product was used directly in the next step without anyfurther purification. ¹H NMR (CDCl₃, 300 MHz) δ 1.09 (s, 9H), 1.22 (t,J=7.5 Hz, 3H), 4.14 (q, J=6.9 Hz, 2H), 4.23 (s, 2H), 7.34-7.47 (m, 6H),7.64-7.79 (m, 4H).

Ethyl (tert-butyldiphenylsilanyloxy)acetaldehyde

To a cooled mixture of ethyl (tert-butyl-diphenylsilanyloxy)acetate(4.98 g, 14.5 mmol) in dichloromethane (20 mL)/hexane (10 mL) was addeddropwise a solution of DIBAL in toluene (1.5 M, 11.6 mL, 17.4 mmol). Theresulting mixture was stirred under N₂ at −70° C. for 1 hour andquenched by adding citric acid solution (1 M, 20 mL) and EtOAc (20 mL).The layers were separated. The aqueous layer was extracted with EtOAc(2×20 mL). The combined organic layers were washed with brine (20 mL),dried (Na₂SO₄), filtered, and concentrated. The crude product wasobtained (4.57 g). ¹H NMR (CDCl₃, 300 MHz) δ 1.07 (s, 9H), 4.23 (d,J=7.8 Hz, 2H), 7.29-7.50 (m, 6H), 7.58-7.85 (m, 4H), 9.73 (s, 1H).

(E)-Ethyl 4-(tert-butyldiphenylsilanyloxy)-2-fluoro-2-butenoate

To a cooled suspension of triethyl 2-fluoro-2-phosphonoacetate (2.96 g,12.2 mmol) in THF (40 mL) was added a solution of isopropylmagnesiumchloride in THF (2.0 M, 7.13 mL, 14.3 mmol). The resulting mixture wasstirred at 0° C. under N₂ for 2 hours, which resulted in a deep redsolution. To this solution was added a solution of ethyl(tert-butyldiphenylsilanyloxy)-acetaldehyde (3.04 g, 10.2 mmol) in THF(10 mL). The resulting mixture was stirred at 0° C. for 5 hours and thenat room temperature overnight. The reaction mixture was quenched withwater (20 mL). The mixture was extracted with EtOAc (3×20 mL). Thecombined organic layers were washed with brine (30 mL), dried (MgSO4),filtered, and concentrated. The residue was purified on flash columnchromatography (silica gel, 1% MTBE/hexane) to give the desired product(2.35 g, 58%). ¹H NMR (CDCl₃, 300 MHz) δ 1.06 (s, 9H), 1.20 (t, J=7.2Hz, 3H), 4.16 (q, J=7.2 Hz, 2H), 4.67 (dd, J=5.4, 3.6 Hz, 2H), 6.11 (dt,J=20.4, 5.4 Hz, 1H), 7.33-7.50 (m, 6H), 7.58-7.75 (m, 4H).

(E)-Ethyl 4-(tert-butyldiphenylsilanyloxy)-2-fluoro-2-butenol

To a cooled solution of ethyl4-(tert-butyldiphenylsilanyloxy)-2-fluoro-2-butenoate (2.8 g, 7.24 mmol)in hexane (20 mL) was added a solution of DIBAL in toluene (1.5 M, 14.5mL, 21.7 mmol). The resulting mixture was stirred at −30° C. under N2for 30 min and then at room temperature for 30 min. The reaction wasquenched with a solution of citric acid (1.0 M, 20 mL). The mixture wasextracted with EtOAc (3×20 mL). The combined organic layers were washedwith brine (20 mL), dried (MgSO4), filtered, and concentrated. Theresidue was purified on flash column chromatography (silica gel, 5%EtOAc/hexane) to give the desired product (0.43 g, 17%). ¹H NMR (CDCl₃,300 MHz) δ 1.04 (s, 9H), 4.04 (dd, J=19.5, 6.6 Hz, 2H), 4.22 (dd, J=7.2,1.8 Hz, 2H), 5.41 (dt, J=20.1, 7.2 Hz, 1H), 7.33-7.52 (m, 6H), 7.61-7.75(m, 4H).

(E)-N-t-Butoxycarbonyl-N-(ethoxyoxoacetyl)-4-(tert-butyldiphenylsilanyloxy)-2-fluoro-2-butenylamine

To a cooled solution of(E)-N-t-butoxycarbonyl-2-fluoro-4-(3-methoxyphenoxy)-2-butenylamine(0.42 g, 1.22 mmol), ethyl N-t-butoxycarbonylaminooxoacetate (0.318 g,1.46 mmol), and PPh3 (0.384 g, 1.46 mmol) in THF (20 mL) was added asolution of DIAD (0.32 g, 1.58 mmol) in THF (5 mL). The resultingmixture was stirred at room temperature overnight, and concentrated invacuo. The residue was purified on flash column chromatography (silicagel, 2% EtOAc/hexane) to provide the desired product (0.535 g, 81%). ¹HNMR (CDCl₃, 300 MHz) δ 1.04 (s, 9H), 1.34 (t, J=6.9 Hz, 3H), 1.46 (s,9H), 4.22-4.38 (m, 6H), 5.42 (dt, J=19.5, 7.2 Hz, 1H), 7.33-7.52 (m,6H), 7.61-7.75 (m, 4H).

(E)-N-t-Butoxycarbonyl-4-(tert-butyldiphenylsilanyloxy)-2-fluoro-2-butenylamine

To a solution of(E)-N-t-Butoxycarbonyl-N-(ethoxyoxoacetyl)-4-(tert-butyldiphenylsilanyloxy)-2-fluoro-2-butenylamine(0.54 g, 0.98 mmol) in THF (10 mL) was added an aqueous solution of LiOH(2.0 M, 2.48 mL, 4.96 mmol). The resulting mixture was stirred at roomtemperature for 3 hours. The layers were separated. The aqueous layerwas extracted with EtOAc (2×10 mL). The combined organic layers werewashed with brine (20 mL), dried (Na₂SO₄), filtered, and concentrated togive crude product (0.44 g, 100%). ¹H NMR (CDCl₃, 300 MHz) δ 1.04 (s,9H), 1.46 (s, 9H), 3.64-3.79 (m, 2H), 4.17-4.30 (m, 2H), 5.31-5.42 (m,1H), 7.34-7.52 (m, 6H), 7.63-7.75 (m, 4H).

(E)-N-t-Butoxycarbonyl-2-fluoro-4-hydroxyl-butenylamine

To a solution of(E)-N-t-butoxycarbonyl-4-(tert-butyldiphenylsilanyloxy)-2-fluoro-2-butenylamine0.43 g, 0.97 mmol) in THF (5 mL) was added tetrabutylammonium fluoridetrihydrate (0.61 g, 1.94 mmol). The mixture was stirred at roomtemperature for 2 hours. The mixture was diluted with water (10 mL) andEtOAc (10 mL). The layers were separated. The aqueous layer wasextracted with EtOAc (2×10 mL). The combined organic layers were washedwith brine (20 mL), dried (Na₂SO₄), filtered, and concentrated. Theresidue was purified on flash column chromatography (silica gel, 30%EtOAc/hexane) to give the desired product (0.18 g, 91%). ¹H NMR (CDCl₃,300 MHz) δ 1.44 (s, 9H), 3.89 (dd, J=21.9, 6.0 Hz, 2H), 4.09-4.20 (m,2H), 5.54 (dt, J=20.1, 7.5 Hz, 1H).

Example 25 Synthesis of Precursors to Compounds of Formula II asDescribed in Scheme 5

General procedure for the preparation of(E)-N-t-Butoxycarbonyl-2-fluoro-4-(substituted-phenoxy)-2-butenylamine:To a cooled mixture of substituted phenol (1.2 eq.), PPh₃ (1.2 eq.), and(E)-N-t-Butoxycarbonyl-2-fluoro-4-hydroxyl-butenylamine (1.0 eq) in THF(20 mL) was added dropwise a solution of DIAD (1.2 eq.) in THF (5.0 mL).The resulting mixture was stirred under N₂ at room temperatureovernight, concentrated in vacuo. The residue was purified on flashcolumn chromatography (silica gel, 5% EtOAc/hexane) to give desiredproduct.

(E)-N-t-Butoxycarbonyl-2-fluoro-4-(3-methoxyphenoxy)-2-butenylamine:(0.22 g, 81%). ¹H NMR (CDCl₃, 300 MHz) δ 1.45 (s, 9H), 3.79 (s, 3H),3.98 (dd, J=20.1, 5.4 Hz, 2H), 4.59 (d, J=6.6 Hz, 2H), 5.52 (dt, J=18.3,7.8 Hz, 1H), 6.42-6.62 (m, 3H), 7.19 (t, J=7.8 Hz, 1H).

(E)-N-t-Butoxycarbonyl-2-fluoro-4-(3-methoxyphenylsulfanyl)-2-butenylamine:(0.1 g, 40%). ¹H NMR (CDCl₃, 300 MHz) δ 1.44 (s, 9H), 3.54 (d, J=8.7 Hz,2H), 3.70 (dd, J=21.9, 7.5 Hz, 2H), 3.81 (s, 3H), 5.32 (dt, J=18.9, 8.4Hz, 1H), 6.76-6.88 (m, 1H), 6.90-7.07 (m, 2H), 7.18-7.26 (m, 1H).

(E)-N-t-Butoxycarbonyl-2-fluoro-4-(3-trifluoromethylphenoxy)-2-butenylamine:(0.31 g, 91%). ¹H NMR (CDCl₃, 300 MHz) δ 1.45 (s, 9H), 4.00 (dd, J=20.4,6.3 Hz, 2H), 4.66 (d, J=7.2 Hz, 2H), 5.52 (dt, J=18.6, 8.1 Hz, 1H),7.04-7.26 (m, 3H), 7.34-7.47 (m, 1H).

(E)-N-t-Butoxycarbonyl-2-fluoro-4-(3-pyridyloxy)-2-butenylamine: (0.13g, 62%). ¹H NMR (CDCl₃, 300 MHz) δ 1.44 (s, 9H), 3.97 (dd, J=20.1, 6.0Hz, 2H), 4.68 (d, J=7.5 Hz, 2H), 5.55 (dt, J=18.9, 8.7 Hz, 1H),7.18-7.26 (m, 2H), 8.20-8.28 (m, 1H), 8.30-8.39 (m, 1H).

Example 26 Synthesis of Compounds of Formula II as Described in Scheme 5

The compounds of Formula II described in this example where preparedfrom Boc-protected products as described in Example 25 using acidicdeprotections as described in Examples 7 and 8.

(E)-2-Fluoro-4-(3-methoxyphenoxy)-2-butenylamine hydrochloride (II-20):(0.13 g, 84%). ¹H NMR (MeOD-d₃, 300 MHz) δ 3.77 (s, 3H), 3.97 (d, J=19.5Hz, 2H), 4.58-4.66 (m, 2H), 5.85 (dt, J=19.5, 6.9 Hz, 1H), 6.47-6.63 (m,3H), 7.19 (t, J=7.8 Hz, 1H). ESMS m/z 212 (M+H)⁺.

(E)-2-Fluoro-4-(3-methoxyphenylsulfanyl)-2-butenylamine hydrochloride(II-21): (0.07 g, 93%). Mp: 88-89° C. ¹H NMR (MeOD-d₃, 300 MHz) δ3.54-3.65 (m, 4H), 3.79 (s, 3H), 5.62 (dt, J=18.9, 8.7 Hz, 1H),6.80-7.05 (m, 3H), 7.25 (t, J=8.1 Hz, 1H). ESMS m/z 228 (M+H)⁺.

(E)-2-Fluoro-4-(3-trifluoromethylphenoxy)-2-butenylamine hydrochloride(II-22): (0.22 g, 86%). ¹H NMR (MeOD-d₃, 300 MHz) δ 3.99 (d, J=19.5 Hz,2H), 4.71 (dd, J=7.2, 1.8 Hz, 2H), 5.89 (dt, J=19.5, 7.2 Hz, lH),7.19-7.34 (m, 3H), 7.50 (t, J=8.4 Hz, 1H). ESMS m/z 250 (M+H)⁺.

(E)-2-Fluoro-4-(3-pyridyloxy)-2-butenylamine hydrochloride (II-23):(0.13 g, 96%). ¹H NMR (MeOD-d₃, 300 MHz) δ 4.04 (d, J=19.5 Hz, 2H),4.91-5.02 (m, 2H), 5.93 (dt, J=18.3, 7.5 Hz, 1H), 7.93-8.06 (m, 1H),8.16-8.28 (m, 1H), 8.42-8.54 (m, 1H), 8.60-8.71 (m, 1H). ESMS m/z 183(M+H)⁺. HRMS Calcd for C₁₂H₁₈ClFNO: 183.0928. Found: 183.0929.

Example 27 In Vitro Inhibition of SSAO Activity

SSAO activity was measured as described (Lizcano J M. Et al. (1998)Biochem J. 331:69). Briefly, rat lung or human umbilical cordhomogenates were prepared by chopping the freshly removed tissue intosmall pieces and washing them thoroughly in PBS. The tissue was thenhomogenized 1:10 (w/v) for lung or 1:5 (w/v) for umbilical cord, in 10mM potassium phosphate buffer (pH 7.8). Homogenates were thencentrifuged at 1000 g at 4° C. for 10 min (lung) or 25,000 g for 30 min(umbilical cord); the supernatants were kept frozen until ready to use.Lung or umbilical cord homogenate was preincubated with clorgyline andpargyline at 1 μM to inhibit MAO-A and -B activity, respectively, andSSAO inhibitors were generally present at 1 nM-10 μM. The reaction wasinitiated by addition of 20 μM ¹⁴C-benzylamine as substrate. Thereaction was carried out at 37° C. in a final volume of 400 μL of 100 mMpotassium phosphate buffer (pH 7.2) and stopped with 100 μl of 2M citricacid. Radioactively labeled products were extracted into toluene/ethylacetate (1:1, v/v) containing 0.6% (w/v) 2,5-diphenyloxazole (PPO)before liquid scintillation counting. Results are shown in Table 1 inthe next example.

Example 28 Comparison of Inhibition of the Activity of SSAO/VAP-1 VersusMAO-A and MAO-B Activities

The specificities of the different SSAO inhibitors was tested bydetermining their abilities to inhibit MAO-A and MAO-B activities invitro. Recombinant human MAO-A and human MAO-B enzymes were obtainedfrom BD Biosciences (MA, USA). MAO activity was measured using thecolorimetric method essentially as described (Holt, A. et al. (1997)Anal. Biochem. 244: 384). A pre-determined amount of inhibitor dilutedin 0.2M potassium phosphate buffer, pH 7.6, was added to each well, ifrequired. The amount of inhibitor varied in each assay but was generallyat a final concentration of between 1 nM and 1 mM. Controls lackedinhibitor. The following agents were then added to a final reactionvolume of 200 μL in 0.2M potassium phosphate buffer, pH 7.6: 0.04 mg/mlof MAO-A or 0.07 mg/ml MAO-B enzyme, 15 μL of 10 mM tyramine substrate(for MAO-A), or 15 μL 100 mM benzylamine substrate (for MAO-B), and 50μL of freshly made chromogenic solution. The chromogenic solutioncontained 750 μM vanillic acid (Sigma#V-2250), 400 μM 4-aminoantipyrine(Sigma #A-4328) and 12 U/mL horseradish peroxidase (Sigma #P-8250) inorder to cause a change of 0.5 OD A490 nm/h. This was within the linearresponse range for the assay. The plates were incubated for 60 min at37° C. The increase in absorbance, reflecting MAO activity, was measuredat 490 nm using microplate spectrophotometer (Power Wave 40, Bio-TekInst.). Inhibition was presented as percent inhibition compared tocontrol after correcting for background absorbance and IC₅₀ valuescalculated using GraphPad Prism software. Clorgyline and pargyline(inhibitors of MAO-A and -B, respectively) at 1 μM, were added to somewells as positive controls for MAO inhibition. The ability of compoundsof the previous Examples to inhibit SSAO activity versus MAO activity isshown in Table 1. The results show that the compounds described in thepresent invention are specific inhibitors of SSAO activity. Thecompounds described in the present invention are therefore expected tohave therapeutic utility in the treatment of diseases and conditions inwhich the activity of SSAO/VAP-1 plays a role, that is, in SSAO/VAP-1mediated diseases and conditions. TABLE 1 Rat Human Human SpecificityHuman Specificity Compound SSAO SSAO MAO-A of SSAO MAO-B of SSAO No:IC50 (μM) IC50 (μM) IC50 (μM) on MAO-A IC50 (μM) on MAO-B I-1-Z 0.0130.018 85 4700 1.6 88 I-2-E 0.008 0.009 85 9400 1.7 189 I-2-Z 0.005 0.0179 7900 12 1200 I-3-Z 0.028 91 3250 0.084 3 I-5-Z 0.028 74 2643 1.8 64.3I-8-E 0.0114 48 4211 35 3070 I-8-Z 0.005 35 7000 27 5400 I-9-Z 0.012 1098385 2.4 200 I-14-E 0.013 77 5923 0.033 2.54 I-14-Z 0.008 90 11250 9.61250 I-15-Z 0.007 119 17000 38 5429 I-19-Z 0.025 34 1360 0.69 27.6I-39-Z 1.2 I-40-Z 0.92 632 687 170 185 I-42-Z 73%@8 mM I-43-Z 1.4 I-44-Z0.72 105 146 16 22 I-45-Z 0.14 20 143 1.2 8.6 I-47-E 0.17 135 794 0.422.5 I-48-E 10 I-49-E 5.5 I-50-E 1 I-51-E 33%@40 mM I-99-Z 0.13 23 1770.27 2.1 I-102-Z 0.03 0.62 21 0.56 19 I-109-Z 0.27 21 78 1.6 5.9 II-1-E0.038 0.036 >87 >2400 >87 >2400 II-3-E 0.45 1000 2222 1000 2222 II-4-E0.51 II-5-E 0.3 >1000 >3333 >1000 >3333 II-6-E 0.13 1000 7692 1000 7692II-7-E 0.22 1000 4545 1000 4545 II-8-E 0.022 1100 50000 1100 50000II-9-E 0.099 1200 12120 1200 12120 II-10-E 0.018 870 48330 966 53670II-11-E 0.11 286 2600 800 7272 II-12-E 55%@7 mM II-13-E 0.01 1000 1000001000 100000 II-14-E 0.07 1000 14290 1000 14286 II-15-E0.023 >800 >34780 >800 >34780 II-17-E 4.5 II-18-E0.29 >1000 >3448 >1000 >3448 II-19-E 0.16 >1000 >6250 850 5312 II-20-E0.75 >1000 >1333 1000 1333 II-21-E 0.088 II-23-E >1000 IV-1 45%@8 mMIV-3 3 IV-8 3.7 IV-10 1.5

Example 29 Inhibition of Collagen-induced Arthritis in Mice

Collagen-induced arthritis (CIA) in mice is widely used as anexperimental model for rheumatoid arthritis (RA) in humans. CIA ismediated by autoantibodies to a particular region of type II collagenand complement. The murine CIA model used in this study is calledantibody-mediated CIA, and can be induced by i.v. injection of acombination of different anti-type II collagen monoclonal antibodies(Terato K., et al. (1995). Autoimmunity. 22:137). Several compounds havebeen used to successfully block inflammation in this model, includinganti-α1β1 and anti-α2β2 integrins monoclonal antibodies (de FougerollesA. R. (2000) J. Clin. Invest. 105: 721).

In this example, arthrogen-collagen-induced arthritis antibody kits werepurchased from Chemicon International (Temecula, Calif.) and arthritiswas induced using the manufacturer's protocol. Mice were injected i.v.with a cocktail of 4 anti-collagen Type II monoclonal antibodies (1.5 mgeach) on day 0, followed by i.p. injection of 25 μg lipopolysaccharide(LPS) on day 2. Mice develop swollen wrists, ankles, and digits 3-4 daysafter LPS injection, with disease incidence of 90% by day 7. Severity ofarthritis in each limb was scored for 3-4 weeks as follows: 0=normal;1=mild redness, slight swelling of ankle or wrist; 2=moderate rednessand swelling of ankle or wrist; 3=severe redness and swelling of somedigits, ankle and paw; 4=maximally inflamed limb, with a maximum scoreof 16 per animal. In the experiment shown in FIG. 4, animals weredivided in 3 groups of 10 animals: vehicle, methotrexate (MTX)-treated,and compound-treated. All treatments were between days 1 and 10, andwere delivered i.p. Animals in the vehicle group were injected withphosphate buffer saline (PBS), once daily for 10 days (starting on day1). MTX (3 mg/kg) was administered starting on day 1 and continuingevery other day (Mon., Weds., Fri.) between days 1 and 10.Administration of compound I-1-Z (30 mg/kg/dose, i.p., one dose daily)was initiated at day 1 and continued until day 10. The results are shownin FIG. 4. The administration of 30 mg/kg of compound I-1-Z, once daily,on days 1-10 clearly reduced the final arthritis score and paw swellingin this model. Statistical analyses were performed by repeated measuresANOVA followed by Dunnett's test for multiple comparisons.

The effect of therapeutic dosing with compound I-1-Z is shown in FIG. 9.Arthritis was induced using the manufacturer's protocol, as describedabove. The Animals were treated with PBS, or with compound I-1-Z at 20mg/kg once daily between day 4 and 13, or with methotrexate at 3 mg/kgon days 4, 6, 8, 10 and 12. All treatments were delivered i.p. Mice weremonitored for clinical signs of arthritis from mild swelling to maximalinflammation of the paw and scored on a pre-defined scale of 1-4 per pawgiving a maximal score of 16 per animal. Statistical analyses wereperformed by repeated measures ANOVA followed by Dunnett's test formultiple comparisons.

The effects of low doses of compound I-1-Z are shown in FIG. 12.Arthritis was induced using the manufacturer's protocol, as describedabove. LPS at 25 μg was given i.p. on day 2. Animals were treated withPBS, or with compound I-1-Z at 1 or 10 mg/kg once daily between days 1and 10, or with methotrexate at 3 mg/kg on days 1, 3, 5, 7 and 9. Alltreatments were delivered i.p. Mice were monitored for clinical signs ofarthritis from mild swelling to maximal inflammation of the paw andscored on a pre-defined scale of 1-4 per paw giving a maximal score of16 per animal. Statistical analyses were performed with repeatedmeasures ANOVA followed by Dunnett's test for multiple comparisons.

Alternate Collagen-induced Arthritis Model in Mice

Collagen-induced arthritis can also be induced by direct injection ofcollagen. Groups of 15 male B10RIII mice were injected intradermallywith Type II collagen in Complete Freund Adjuvant (CFA) on days 0 and15. Mice were dosed p.o. starting from day 0 to day 28 with phosphatebuffered saline (PBS), 5 mg/kg compound I-1-Z, 30 mg/kg compound I-1-Zor 0.2 mg/kg dexamethasone. The results are shown in FIG. 15. CompoundI-1-Z at 5 mg/kg reduced both the incidence of arthritis and theclinical scores as compared to PBS; however, no clinical efficacy wasobserved when animals were dosed with compound I-1-Z at 30 mg/kg.Clinical scores were determined daily for each paw based on a scalebetween 0-5 based on joint erythema and swelling. Statistical analysiswas by Student's t-test versus the PBS-treated disease control group.

Example 30 Inhibition of Experimental Autoimmune Encephalomyelitis inMice by SSAO Inhibitors

SSAO/VAP-1 is expressed on the endothelium of inflamed tissues/organsincluding brain and spinal cord. Its ability to support lymphocytetransendothelial migration may be an important systemic function ofSSAO/VAP-1 in inflammatory diseases such as multiple sclerosis andAlzheimer's disease. An analysis of the use of SSAO inhibitors to treatinflammatory disease of the central nervous system (CNS) was performedthrough the use of an experimental autoimmune encephalomyelitis model(EAE) in C57BL/6 mice. EAE in rodents is a well-characterized andreproducible animal model of multiple sclerosis in human (Benson J. M.et al. (2000) J. Clin. Invest. 106:1031). Multiple sclerosis is achronic immune-mediated disease of the CNS characterized by patchyperivenular inflammatory infiltrates in areas of demyelination andaxonal loss. As an animal model, EAE can be induced in mice byimmunization with encephalitogenic myelin antigens in the presence ofadjuvant. The pathogenesis of EAE comprises presentation of myelinantigens to T cells, migration of activated T cells to the CNS, anddevelopment of inflammation and/or demyelination upon recognition of thesame antigens.

To examine the role of SSAO/VAP-1 as a major regulator of the lymphocyterecruitment to the CNS, compound II-1-E, an SSAO inhibitor, wasevaluated in an EAE model.

Twenty female C57BL/6 mice were immunized subcutaneously (s.c). withmyelin oligodendrocyte glycoprotein 35-55 (MOG peptide 35-55) inComplete Freund Adjuvant (CFA) on day 0, followed by i.p. injections of500 ng pertussis toxin (one pertussis toxin injection on day 0, a secondpertussis toxin injection on day 2). Groups of 10 mice received eithercompound II-1-E 40 mg/kg/dose, once daily i.p. for 30 consecutive days),or vehicle control (once/day for 30 consecutive days) all starting fromone day after the immunization and all administered i.p. The animalswere monitored for body weight, signs of paralysis and death accordingto a 0-5 scale of scoring system as follows: 1=limp tail or waddlinggait with tail tonicity; 2=waddling gait with limp tail (ataxia);2.5=ataxia with partial limb paralysis; 3=full paralysis of one limb;3.5=full paralysis of one limb with partial paralysis of second limb;4=full paralysis of two limbs; 4.5=moribund; 5=death. Results are shownin FIG. 3. In the control group, disease reached 100% incidence at day13, compared with day 24 for the compound II-1-E-treated group. Inaddition, from day 14 onward the mean clinical score of the treatedgroup was well below that in the control group, and similar clinicalscores between the two groups was not reached until day 38.

Example 31 Inhibition of Carrageenan-induced Rat Paw Edema

Carrageenan-induced paw edema has been extensively used in theevaluation of anti-inflammatory effects of various therapeutic agentsand is a useful experimental system for assessing the efficacy ofcompounds to alleviate acute inflammation (Whiteley P E and Dalrymple SA, 1998. Models of inflammation: carrageenan-induced paw edema in therat, in Current Protocols in Pharmacology. Enna S J, Williams M, FerkanyJ W, Kenaki T, Porsolt R E and Sullivan J P, eds., pp 5.4.1-5.4.3, JohnWiley & Sons, New York). The full development of the edema isneutrophil-dependent (Salvemini D. et al. (1996) Br. J. Pharmacol. 118:829).

Female Sprague Dawley rats were used in groups of 8-12 and compounds ofthe invention were administered orally at up to 50 mg/kg 60 min prior tocarrageenan exposure. The control group was administered orally an equalvolume of vehicle (PBS). Edema in the paws was induced as previouslydescribed by injecting 50 μL of a 0.5% solution of carrageenan (Type IVLambda, Sigma) in saline with a 27-G needle s.c. in the right foot pad.(See Whiteley P. E. and Dalrymple S. A. (1998), Models of inflammation:carrageenan-induced paw edema in the rat, in Current Protocols inPharmacology, Enna S J, Williams M, Ferkany J W, Kenaki T, Porsolt R Eand Sullivan J P, eds., pp 5.4.1-5.4.3, John Wiley & Sons, New York) Thesize of the tested foot of each animal was measured volumetrically witha plethysmometer immediately after injection of carrageenan solution andat various times up to 360 min after carrageenan induction.

Results of experiments with the compounds II-1-E, I-1-Z, and I-2-Z areshown in FIG. 1, FIG. 5, and FIG. 6, respectively. In each case the 50mg/kg dose clearly reduced the paw swelling between 2-6 h (CompoundII-1-E and Compound I-1-Z), and between 3-6 h for Compound I-2-Z. FIG. 1also shows comparison to (2-phenylallyl)hydrazine at 50 mg/kg, whileFIG. 5 and FIG. 6 show comparison to indomethacin (3 mg/kg).

FIG. 7 shows a dose response effect of compound I-1-Z oncarrageenan-induced paw edema in the rats. Using the same procedurediscussed above, the size of the foot of each animal was measuredvolumetrically before induction of edema, and at 1.5, 3, 4.5 and 6 hafter the carrageenan injection. The absolute decreases in paw swellingat 6 h with 1, 10 and 50 mg/kg were 5±11%, 20±9% and 32±6% respectively.Statistical analyses were performed with repeated measures ANOVAfollowed by Dunnett's test for multiple comparisons.

FIG. 8 shows the effect of therapeutic dosing with compound I-1-Z oncarrageenan-induced paw edema in the rats. Paw edema was induced ingroups of eight Sprague Dawley rats by injecting 50 μL of a 0.375%solution of carrageenan λ in saline, subcutaneously in the foot. Afterone hour animals were orally dosed once with PBS, compound I-1-Z at 50mg/kg or with itidomethacin at 3 mg/kg. The size of the paws weremeasured before induction of edema (baseline), and at 1.5, 3, 4.5 and 6h after carrageenan injection. The magnitude of inhibition steadilyincreased up to 6 h, to give 50±4% inhibition by compound I-1-Z and67±8% by indomethacin at 6 h. Statistical analyses were performed withrepeated measures ANOVA followed by Dunnett's test for multiplecomparisons.

FIG. 13 shows the effect of low doses of compound I-1-Z oncarrageenan-induced paw edema in the rats. Groups of eight SpragueDawley rats were orally administered PBS, or 0.01, 0.1 or 1 mg/kg ofcompound I-1-Z. One hour later paw edema was induced in all animals byinjecting 50 μL of a 0.5% solution of carrageenan λ in saline,subcutaneously into the footpad. The size of the foot of each animal wasmeasured volumetrically before induction of edema, and at 1.5, 3, 4.5and 6 h after the carrageenan injection. The absolute decreases in pawswelling at 6 h with 0.1 and 1 mg/kg were 34±8 and 29±8% respectively.Statistical analyses were performed with repeated measures ANOVAfollowed by Dunnett's test for multiple comparisons.

Example 32 Inhibition of Oxazolone-induced Colitis

Oxazolone-induced colitis is a TH2-mediated process that closelyresembles ulcerative colitis and is responsive to anti-IL4 therapy((Strober W. et al (2002) Annu. Rev. Immunol. 20: 495, Boirivant M. etal. (1998) J. Ex. Med. 188: 1929). Oxazolone colitis is induced asdescribed (Fuss I. J. et al. (2002) J. Immunol. 168: 900). Briefly, miceare pre-sensitized by epicutaneous application of 1% oxazolone(4-ethoxymethylene-2-phenyl-2oxazolin-5-one, Sigma) in 100% EtOH (200μL) on day 0, followed by intrarectal administration of 0.75% oxazolonein 50% EtOH (100 μL) to anesthetized SJL/J male mice on day 5 through a3.5 F catheter inserted 4 cm proximal to the anal verge. Mice aredivided in two treatment groups and injected i.p. twice a day witheither PBS or a compound of the invention. Injections are initiated atday 0 and are continued through day 12. Disease progression is evaluatedby monitoring body weight and survival.

A study was carried out using the protocol described above foroxazolone-induced colitis. Compound II-1-E at 30 mg/kg or bufferinjections, administered intraperitoneally were initiated at day 0 andwere continued until day 12. Disease progression was evaluated until day15 (10 days after intrarectal administration) by monitoring survivalrates and body weight. When following the above-described protocol,disease severity as measured by body weight drop was maximal at day 11(6 days after intrarectal challenge), although animals started dying onday 9. Results showed that compound II-1-E improved survival rates andbody weight loss when compared with the vehicle group; see FIG. 2A andFIG. 2B.

Example 33 Acute Toxicity Studies

Oral (p.o.) and intravenous (i.v.) LD₅₀ values for the compounds of theinvention are determined in mice. Six-week old C57B1/6 female mice aredivided in groups of five and administered a single i.v., p.o. or i.p.injection of compound dissolved in PBS (10-100 mg/kg in 100 μL i.v.;30-1000 mg/kg p.o.; 30-500 mg/kg in 200 μL i.p.). Control groups areadministered the same volume of PBS i.p., p.o. or i.v. Appearance andovert behavior are noted daily, and body weight is measured beforecompound administration (Day 1) and on Days, 3, 5 and 7. After sevendays, animals are euthanized and their liver, spleen, and kidneys areweighed.

Example 34 Inhibition of Concanavalin A-induced Liver Injury

Prevention of inflammation by administration of compounds of theinvention is assessed in the concanavalin A (Con A) murine model ofliver injury. Con A activates T lymphocytes and causes T cell-mediatedhepatic injury in mice. Tumor necrosis factor alpha is a criticalmediator in this experimental model. T-cell-mediated liver injuryinvolves the migration of immune cells, notably CD4+ T lymphocytes, intoliver tissue. Balb/c mice are inoculated with 10 mg/kg concanavalin Aadministered i.v. in 200 μL pyrogen-free saline as described (WilluweitA. et al. (2001) J Immunol. 167:3944). Previous to Con A administration,animals are separated into treatment groups and injected i.p with PBS,or with different concentrations of compound of the invention (e.g., 20mg/kg). Liver damage is evaluated by determining serum levels of liverenzymes such as transaminase and alkaline phosphatase, hepatichistopathology, and levels of different inflammatory cytokines in plasmaand liver tissue.

This procedure is used to screen for compounds which inhibit thedevelopment of liver damage as compared to control animals.

Example 35 Effect of Compounds of the Invention in a Mouse Model ofAlzheimer's Disease

Alzheimer's disease (AD) is characterized clinically by a dementia ofinsidious onset and pathologically by the presence of numerous neuriticplaques and neurofibrillary tangles. The plaques are composed mainly ofβ-amyloid (Aβ) peptide fragments, derived from processing of the amyloidprecursor protein (APP). Tangles consist of paired helical filamentscomposed of the microtubule-associated protein, tau. Transgenic micecarrying a pathogenic mutation in APP show marked elevation ofAβ-protein level and Aβ deposition in the cerebral cortex andhippocampus from approximately 1 year of age (Hsiao K. et al. (1996)Science 274:99). Mutant PS-1 transgenic mice do not show abnormalpathological changes, but do show subtly elevated levels of the A1342/43peptide (Duff K, et al. (1996) Nature 383:710). Transgenic mice derivedfrom a cross between these mice (PS/APP) show markedly acceleratedaccumulation of Aβ into visible deposits compared with APP singlytransgenic mice (Holcomb L. et al. (1998) Nat Med 4:97). Further, arecent study indicates that in these mice, inflammatory responses may beinvolved in the Aβ depositions (Matsuoka Y. et al. (2001) Am J Pathol.158(4): 1345).

The PS/APP mouse, therefore, has considerable utility in the study ofthe amyloid phenotype of AD and is used in studies to assess efficacy ofthe compounds of the invention to treat Alzheimer's patients. Mice areinjected with vehicle (e.g., PBS) or a compound of the invention (at,e.g., 10-20 mg/kg), and are evaluated by analysis of memory deficits,histological characteristics of sample tissues, and other indicators ofdisease progression.

Alternate Alzheimer's Model: Assessing Efficacy in Amyloid-B-inducedAutoimmune Encephalitis

The abnormal processing and extracellular deposition of amyloid-B (Aβ)peptide, is a defining characteristic of Alzheimer's disease (AD).Recent evidence suggests that vaccination of transgenic mouse models ofAD with Aβ causes a marked reduction in brain amyloid burden (e.g.Schenk D et al. (1999) Nature 400:173). Moreover, a recently publishedreport suggests that vaccination with Aβ can, in certain circumstances,determine an aberrant autoimmune reaction to Aβ within the CNS,resulting in a perivenular inflammatory encephalomyelitis (Furlan R etal. (2003) Brain 126:285).

Evaluation of the efficacy of compounds of the invention is carried outin the Aβ-induced autoimmune encephalomyelitis model. Thirty femaleC57BL/6 mice are immunized subcutaneously (s.c). with 100 μg of Aβ1-42peptide in Complete Freund Adjuvant (CFA) on day 0, followed by i.p.injections of pertussis toxin (one pertussis toxin injection on day 0, asecond pertussis toxin injection on day 2). Groups of 10 mice receiveeither a compound of the invention (10 mg/kg/dose, twice daily for 18consecutive days), methotrexate (2.5 mg/kg/day, three times a week, tillday 18) or vehicle control (twice/day for 18 consecutive days), allstarting from one day after the immunization and all administered i.p.Then animals are monitored for body weight, signs of paralysis and deathaccording to a 0-5 scale of scoring system as follows: 1=limp tail orwaddling gait with tail tonicity; 2=waddling gait with limp tail(ataxia); 2.5=ataxia with partial limb paralysis; 3=full paralysis ofone limb; 3.5=full paralysis of one limb with partial paralysis ofsecond limb; 4=full paralysis of two limbs; 4.5=moribund; 5=death.

Example 36 Effect of Compounds of the Invention in Murine Models of TypeI Diabetes Mellitus

It is widely accepted that proinflammatory cytokines play an importantrole in the development of Type I diabetes. Thus, compounds of theinvention can be used to treat patients suffering from this disease. Amouse with diabetes induced by multiple low doses of streptozotocin(STZ) can be used as an animal model for Type I diabetes. STZ is used toinduce diabetes in C57BL/6J mice. Briefly, STZ (40 mg/kg) or citratebuffer (vehicle) is given i.p. once daily for 5 consecutive days asdescribed (Carlsson P. O. et al. (2000) Endocrinology. 141(8):2752).Compound administration (i.p. 10 mg/kg, twice a day) is started 5 daysbefore STZ injections and continues for 2 weeks. Another widely usedmodel is the NOD mouse model of autoimmune Type I diabetes (Wong F. S.and Janeway C. A. Jr. (1999) Curr Opin Immunol. 11(6):643. Female NODmice are treated with daily injections of a compound of the invention(20 mg/kg/day) from week 10 through week 25. The effect of the compoundsof the invention in preventing the development of insulitis and diabetesin NOD-scid/scid females after adoptive transfer of splenocytes fromdiabetic NOD females is also assessed. For both the STZ and NOD models,the incidence of diabetes is monitored in several ways, includingmonitoring of blood glucose levels. Insulin secretion is assessed inpancreatic islets isolated from experimental mice. Cytokine productionis measured in mouse sera. Islet apoptosis is assessed quantitatively.

This procedure is used to screen for compounds which inhibit developmentof diabetes as compared to control animals.

Example 37 Effect of Compounds of the Invention in Models of AirwayInflammation

Anti-inflammatory compounds such as SSAO inhibitors can have beneficialeffects in airway inflammatory conditions such as asthma and chronicobstructive pulmonary disease. The rodent model here described has beenextensively used in efficacy studies. Other murine models of acute lunginflammation can also be used to test the compounds of the invention.

For the evaluation of the effects of SSAO inhibitors in preventingairway inflammation, three groups of sensitized rats are studied.Animals are challenged with aerosolized OVA (ovalbumin) afterintraperitoneal administration of the vehicle saline, a compound of theinvention, or a positive control (e.g. prednisone) twice daily for aperiod of seven days. At the end of the week animals are anesthetizedfor measurements of allergen-induced airway responses as described(Martin J. G. et al. (2002) J Immunol. 169(7):3963). Animals areintubated endotracheally with polyethylene tubing and placed on aheating pad to maintain a rectal temperature of 36° C. Airflow ismeasured by placing the tip of the endotracheal tube inside a Plexiglasbox (˜250 mL). A pneumotachograph coupled to a differential transduceris connected to the other end of the box to measure airflow. Animals arechallenged for 5 min with an aerosol of OVA (5% w/v). A disposablenebulizer will be used with an output of 0.15 mL/min. Airflow ismeasured every 5 min for 30 min after challenge and subsequently at 15min intervals for a total period of 8 h. Animals are then sacrificed forbronchoalveolar lavage (BAL). BAL is performed 8 h after challenge withfive instillations of 5 mL of saline. The total cell count and cellviability is estimated using a hemacytometer and trypan blue stain.Slides are prepared using a Cytospin and the differential cell count isassessed with May-Grunwald-Giemsa staining, and eosinophil counts byimmunocytochemistry.

Alternate Model of Airway Inflammation: Assessing the Effect ofCompounds of the Invention

LPS-induced pulmonary inflammation in rats is a widely used model ofairway inflammation (e.g. Billah M et al.(2002) J. Pharmacol. Exp. Ther.302:127). For the experiment described here, groups of Sprague-Dawleyfemale rats (180-200 g) were orally dosed with either a compound of theinvention (1 or 10 mg/kg), or with vehicle 1 h before the LPS challenge.Animals were placed in a plexiglass chamber and LPS at 100 μg/ml wasnebulized for ten minutes. The nebulizer was turned off for ten minutes,then the chamber was evacuated for a further ten minutes. The animalsremained in the chamber throughout this 30 minute cycle. Animals werethen returned to their cages for the remainder of the experiment. Fourhours after exposure to LPS animals were sacrificed and lungs excised.Lungs were washed with three cycles of 3 ml RPMI 1640 medium and thelavage fluid combined. Cells were pelleted by centrifugation and washedin the same medium.

Total cell counts were performed using a hemacytometer. Differentialcell counts were conducted on Cytospin-prepared slides stained withDiff-Quick stain. Standard morphological criteria were used to definemononuclear and neutrophilic cells.

Using the above protocol, an experiment to assess the effects ofcompound I-1-Z was carried out. Groups of four female Sprague Dawleyrats were orally administered PBS, compound I-1-Z at the indicateddoses, or dexamethasone at 3 mg/kg. Rats were then exposed to nebulizedLPS for 30 minutes. Four hours later rats were sacrificed, and cellsharvested from lungs by bronchioalveolar lavage. Approximately 5×10⁵alveolar macrophages were harvested from lungs of animals not exposed toLPS, and 90-95% of LPS-induced cells were neutrophils. Statisticalanalysis was performed by one way ANOVA followed by Dunnett's test formultiple comparisons. The results are shown in FIG. 14, and indicatethat doses of 1 mg/kg or 10 mg/kg of compound I-1-Z are effective inreducing LPS-induced lung inflammation..

Example 38 Efficacy in Model of Systemic Inflammation

Evaluation of the efficacy of compounds of the invention is carried outin a model of endotoxemia (Pawlinski R et al. (2003) Blood 103:1342).Sixteen female C57Bl/6 mice (eight to ten weeks old) are divided in twotreatment groups: group A animals are administered 500 μL of PBS orally;group B animals are administered 100 mg/kg of a compound of theinvention in 500 μL of PBS orally. 30 min after oral administration ofcompound, inflammation is induced in all animals by administering i.p. 5mg/kg of LPS (O111:B4, Sigma) in PBS. Blood samples (˜50 μL) arecollected from the retro-orbital sinus at 0 (before oral administrationof compound), 1, 2, 4, and 8 h after LPS injection. Each sample isimmediately diluted ½ in PBS. Half of the diluted sample is used toprepare blood smear and the other 50 μL is centrifuged and serum iscollected. Sera samples are used to determine IL1, IL6 and TNFa levelsby ELISA. Animal survival rates are recorded for the next 3 days.

Example 39 Inhibition of Cutaneous Inflammation in the SCID Mouse Modelof Psoriasis

Recent establishment of the SCID-human skin chimeras with transplantedpsoriasis plaques has opened new vistas to study the molecularcomplexities involved in psoriasis. This model also offers a uniqueopportunity to investigate various key biological events such as cellproliferation, homing in of T cells in target tissues, inflammation andcytokine/chemokine cascades involved in an inflammatory reaction. TheSCID mouse model has been used to evaluate the efficacy of severalcompounds for psoriasis and other inflammatory diseases (Boehncke W. H.et al. (1999) Arch Dermatol Res. 291(2-3):104).

Transplantations are to be done as described previously (Boehncke, W. H.et al. (1994) Arch. Dermatol. Res. 286:325). Human full-thicknessxenografts are transplanted onto the backs of 6- to 8-week-old C.B17SCID mice (Charles River). For the surgical procedure, mice areanesthetized by intraperitoneal injection of 100 mg/kg ketamine and 5mg/kg xylazine. Spindle-shaped pieces of full-thickness skin measuring 1cm in diameter are grafted onto corresponding excisional full-thicknessdefects of the shaved central dorsum of the mice and fixed by 6-0atraumatic monofilament sutures. After applying a sterile petroleumjelly-impregnated gauze, the grafts are protected from injury bysuturing a skin pouch over the transplanted area using the adjacentlateral skin. The sutures and over-tied pouches are left in place untilthey resolve spontaneously after 2-3 weeks. Grafts are allowed 2 weeksfor acceptance and healing. Thereafter, daily intraperitoneal injectionsare performed between days 15 and 42 after transplantation. Mice areinjected with either vehicle (PBS), dexamethasone (0.2 mg/kg bodyweight), or a compound of the invention (at, e.g., 20 mg/kg body weight)in a final volume of 200 μL. Mice are sacrificed at day 42, and afterexcision with surrounding mouse skin the grafts are formalin-embedded.Subsequently, routine hematoxylin-and-eosin staining is performed, andthe grafts are analyzed with regard to their pathological changes bothqualitatively (epidermal differentiation, inflammatory infiltrate) andquantitatively (epidermal thickness).

Example 40 Oral Bioavailability Studies in Rodents

Oral bioavailability studies in mice and rats are to be performed usingthe following procedure. Briefly, C57Bl/6 female mice and Sprague Dawleyfemale rats are administered 50 mg/kg of different compounds of theinvention by oral gavage. Animals are bled at different time intervalsafter compound administration and the levels of inhibitor in plasma aredetermined using the colorimetric assay described in Example 28 above.

Example 41 Dose-response Effect From In Vivo Administration ofSSAO/VAP-1 Inhibitors

In vivo inhibition of SSAO is assessed in rat aorta and lungs, two ofthe tissues where SSAO activity is highest. Six week old female SpragueDawley rats are to be administered 0, 0.1, 1, 10 and 50 mg/kg of acompound of the invention in 2.5 mL/kg PBS by oral gavage. Four hoursafter compound administration the animals are euthanized and theiraortas and lungs are removed and frozen in liquid nitrogen. Tissues arehomogenized in 0.01M potassium phosphate pH 7.8, and used to measureSSAO activity in the radioactive assay following the protocol describedby Lizcano J. M. et al. (1998) Biochem. J. 331:69. Details of the assayare given in Example 27 above.

Example 42 Blocking of In Vitro Adhesion by SSAO/VAP-1 Inhibitors

These studies are carried out in order to determine whether SSAO/VAP-1transfected into endothelial cells will retain the adhesion function andwhether it plays any role in the adhesion of freshly isolated humanPBMCs to these cells. Moreover, the studies are also designed todetermine whether blocking of SSAO/VAP-1 will have an impact on thelevel of adhesion between these two cell types. Adhesion assays areperformed using cells labeled with the fluorescent dye Calcein-AM(Molecular Probes, OR, USA) as per the manufacturer's instructions.Briefly, rat lymph node high endothelial cells (HEC; isolation andculture is described in Ager, A. (1987) J. Cell Sci. 87: 133) are platedovernight in 96-well plates (2,000 cells/well). PBMCs (peripheral bloodmononuclear cells) (1×10⁷) are labeled with 1 mL of 10 μM Calcein-AM for1 h at 37° C., washed three times with RPMI, and added to the 96 wellplates containing monolayers of HEC cells mock-transfected ortransfected with full-length human SSAO/VAP-1 (60,000 PBMCs were platedper well containing 2,000 HEC cells). Adhesion is carried out for 3 h at37° C. Non-adherent cells are removed by washing three times with RPMIand fluorescence is measured in a fluorescence plate reader at anexcitation wavelength of 485 nm and emission wavelength of 530 nm.Several controls are to be included, such as HEC cells and PBMCs(labeled and unlabeled) alone.

The next experiments are designed in order to investigate whetherblocking the enzymatic catalytic site will have any effect on theadhesion function of SSAO/VAP-1, and whether or not inhibitors accordingto the invention will mediate an adhesion-inhibiting effect. Publishedresults suggest that blocking SSAO enzymatic activity with semicarbazideinhibited lymphocyte rolling under laminar sheer on cardiac endothelialmonolayers (Salmi et al. Immunity (2001) 14:265). These studies can thusbe repeated using the adhesion assay as described above to evaluate theinhibitors of the invention. Adhesion blockers can include an anti-humanVAP-1 monoclonal antibody (Serotec, Oxford, UK), neuramidase (asialidase, because SSAO/VAP-1 is a sialoglycoprotein; Sigma), andseveral function-blocking antibodies to rat adhesion molecules(CD31-PECAM, CD54-ICAM-1, CD92P-P Selectin). Controls can include theSSAO inhibitor semicarbazide (Sigma), MAO-A and MAO-B inhibitors(clorgyline and pargyline, respectively; Sigma), and mouse IgG1 and IgG2isotype controls (BD, USA). Antibodies (10 μg/ml) and neuramidase (5 mU)are incubated with the HECs for 30 min at 37° C.; excess antibody iswashed away prior to the addition of the labeled PBMCs. Small-moleculeinhibitors are pre-incubated the same way at IC₁₀₀ concentrations, butthe amounts present in the supernatant are not washed away to preservethe IC₁₀₀ concentration during the adhesion step.

Example 43 Effect of Therapeutically Administered I-1-Z on CellTrafficking

Air pouches were introduced, on day 1, into the back of groups of eightC57BL/6 mice by subcutaneous injection of filtered air. On day 2 the airpouches were injected with 0.5 ml of 1% carrageenan. Four hours latermice were administered: PBS, LJP 1586 at 1 or 10 mg/kg orally, or ratIgG2a antibody or anti-LFA-1 at 100 μg intravenously. Sixteen hourslater the mice were sacrificed, cells removed by lavage and counted.Statistical analyses were performed using one-way ANOVA followed byDunnett's test for multiple comparisons. The results are shown in FIG.10.

Example 44 Effect of Route ofAdministration of I-1-Z on Cell Trafficking

Air pouches were introduced onto mice as described in Example 43 (n=8).Twenty-four hours later mice were administered: PBS p.o. or 10 mg/kg LJP1586, either p.o. or i.p., or 100 μg rat IgG2a antibody or anti-LFA-1,both intravenously. One hour later the air pouches were injected with0.5 ml of 1% carrageenan and 24 hours later the mice were sacrificed,cells removed by lavage and counted. Statistical analyses were performedusing one-way ANOVA followed by Dunnett's test for multiple comparisons.The results are shown in FIG. 16.

Example 45 ED50 of Compound I-1-Z for Rat Lung SSAO

Groups of five Sprague Dawley rats were orally administered theindicated doses of compound I-1-Z. At 1, 3, 6 or 24 h later, the animalswere sacrificed, lungs excised and SSAO activity in lung homogenatesdetermined. Results are presented as percent inhibition of SSAO activityrelative to animals that were administered PBS. The results are shown inFIG. 11. The ED50 for inhibition of rat lung SSAO activity by compoundI-1-Z is between 0.1 mg/kg and 1 mg/kg.

Example 46 Comparison of Inhibition of the SSAO Activity of SSAO/VAP-1Versus DAO

Compounds of the invention can be tested for their inhibitory activityagainst diamine oxidase (DAO). Recombinant DAO was expressed in CHOcells using standard molecular biology methods as described herein.

The DNA sequence for DAO (AOC1, NM-001091) was synthetically produced byGenscript Corp. A codon-optimized DAO sequence was subdloned into themammalian expression vector pcDNA5/FRT. CHO cells with a stable genomeintegrated FLP recombination site allow Frt recombinase mediatedintegration into a stable transcriptionally active site in the genome.The pcDNA5/FRT containing DAO was cotransfected with pOGG44, a vectorthat encodes the Frt recombinase at a ration of 1:50 using a total of ˜1ug of DNA to transfect ˜1E4 cells by the Fugene method. Cells werecultured in F-12K media with 10% FBS containing media containing 0.5mg/ml Hygromycin until single colonies emerged. Single colonies werepicked and grown individually in a 24 well culture plate untilconfluent. Samples of the media were taken and screened for enzymaticactivity using 1,4-diaminobutane as substrate in an AMPLEX Red-basedperoxide detection assay. Positive expression clones, compared to mediafrom mock transfected cells which show no activity above background,were expanded and grown in larger quantities in serum containing mediauntil ˜80% confluent. The serum containing media was removed and thecells were switched to CHO SFM serum free media for 48 hours. The mediacontaining enzymatic activity displayed a prominent single band ofapproximately 78 kD on denaturing SDS-PAGE. Naive CHO SFM media and mocktransfection incubated media did not display this signal. The media wascollected and used directly as a source of diarniine oxidase for enzymeanalysis. The enzyme as prepared by this method was inhibited at an IC₅₀of approximately 12.5 nM by aminoguanidine, similar to values reportedin the literature for aminoguanidine inhibition of diamine oxidase(Bieganski et al., Biochim. Biophys. Acta. 756:196 (1983); Holt & Baker,Prog. Brain Res. 106:187 (1995)).

Inhibition of diamine oxidase was determined by using the AMPLEX RedMonoamine Oxidase assay sold by Invitrogen (Carlsbad, Calif.) (AMPLEX isa registered trademark of Molecular Probes, Inc., Eugene Oreg., forfluorogenic chemicals and enzyme-coupled assays for use in scientificresearch.) The assay protocol was used, with the substitution of diamineoxidase for monoamine oxidase and the substitution of putrescine(1,4-diaminobutane) for the benzylamine/tyramine substrate. (See Nicotraet al., Biogenic Amines 15, 307 (1999); Zhou et al., Anal. Biochem. 253,162-168 (1997); Zhou et al., Anal. Biochem. 253, 169-174 (1997); Holt etal., Anal. Biochem. 244:384-92 (1997); Hall et al., Biochem. Pharmacol.18:1447-54 (1969); and Youdim et al., Methods Enzymol. 142:617-27(1987).)

The specificity of compound I-1-Z for human SSAO versus human diamineoxidase (DAO) was tested. Compound I-1-Z has an IC₅₀ for human SSAO of0.018 uM, as reported above. The IC₅₀ of compound I-1-Z for human DAO is92 uM. The IC₅₀ for DAO divided by the IC₅₀ for SSAO of compound I-1-Zis about 5,111, indicating that compound I-1-Z is about 5,000 times morespecific for SSAO than for DAO.

Example 47 Screening for Receptors Affected by SSAO Inhibitor

A screening procedure was employed to determine whether compound I-1-Zaffects specific ligand binding to various receptors. Ligand binding tothe following receptors was not affected by a 10 μM concentration ofcompound I-1-Z:

Non-Peptide Receptors: Adenosine, Adrenergic, Benzodiazepine,Cannabinoid, Dopamine, GABA, Glutamate, Histamine, Melatonin,Muscarinic, Prostanoid, Purinergic, Serotonin, Sigma;

Peptide Receptors: Angiotensin II, Bombesin, Bradykinin,Calcitonin-related peptide, Chemokine, Cholecystokinin, Cytokine,Endothein, Galanin, Growth factor, Melanocortin, Neurokinin,Neuropeptide Y, Neurotensin, Opioid, Somatostatin, VIP, Vasopressin;

Ion Channels: Calcium, Potassium, Sodium.

Ligand binding to the following receptors was affected by a 10 μMconcentration of compound I-1-Z:

5-HT_(1A) (34% inhibition);

Amine transporters: Dopamine (38% inhibition), Norepinephrine (68%inhibition), Serotonin (47% inhibition).

Table 2, below, shows receptors that were tested for their potentialinteraction., and includes the reference compound and shortbibliographic reference for the assay. Table 3, below, providesadditional information about the assay conditions. Table 4, below,reports the summary data in terms of the percentage by which compoundI-1-Z inhibited binding of the reference compound to the receptor. Theabbreviation (h) in the tables below indicates that the human receptorwas used. Table 2-A, Table 2-B, Table 2-C, and Table 2-D provideadditional information about the receptors. TABLE 2 Receptor AssayOrigin Reference Compound Bibliography A₁ (h) human recombinant DPCPXTownsend-Nicholson and (CHO cells) Schofield (1994) A_(2A) (h) humanrecombinant NECA Luthin et al. (1995) (HEK-293 cells) A₃ (h) humanrecombinant IB-MECA Salvatore et al. (1993) (HEK-293 cells) α₁(non-selective) rat cerebral cortex prazosin Greengrass and Bremner(1979) α₂ (non-selective) rat cerebral cortex yohimbine Uhlen andWikberg (1991) β₁ (h) human recombinant atenolol Levin et al. (2002)(HEK-293 cells) β₂ (h) human recombinant ICI 118551 Smith and Teitler(1999) (Sf9 cells) AT₁ (h) human recombinant saralasin Bergsma et al.(1992) (CHO cells) AT₂ (h) human recombinant saralasin Tsuzuki et al.(1994) (Hela cells) BZD (central) rat cerebral cortex diazepam Speth etal. (1979) BZD (peripheral) rat heart PK 11195 Le Fur et al. (1983) BB(non-selective) rat cerebral cortex bombesin Guard et al. (1993) B₂ (h)human recombinant NPC 567 Pruneau et al. (1998) (CHO cells) CGRP (h)human recombinant hCGRPα Aiyar et al. (1996) (CHO cells) CB₁ (h) humanrecombinant CP 55940 Rinaldi-Carmona et al. (1996) (CHO cells) CCK_(A)(h) (CCK₁) human recombinant CCK-8 Bignon et al. (1999) (CHO cells)CCK_(B) (h) (CCK₂) human recombinant CCK-8 Lee et al. (1993) (CHO cells)D₁ (h) human recombinant SCH 23390 Zhou et al. (1990) (CHO cells) D_(2S)(h) human recombinant (+)butaclamol Grandy et al. (1989) (HEK-293 cells)D₃ (h) human recombinant (+)butaclamol Mackenzie et al. (1994) (CHOcells) D_(4.4) (h) human recombinant clozapine Van Tol et al. (1992)(CHO cells) D₅ (h) human recombinant SCH 23390 Sunahara et al. (1991)(GH4 cells) ET_(A) (h) human recombinant endothelin-1 Buchan et al.(1994) (CHO cells) ET_(B) (h) human recombinant endothelin-3 Fuchs etal. (2001) (CHO cells) GABA (non-selective) rat cerebral cortex GABATsuji et al. (1988) GAL1 (h) human recombinant galanin Sullivan et al.(1997) (HEK-293 cells) GAL2 (h) human recombinant galanin Bloomquist etal. (1998) (CHO cells) PDGF Balb/c 3T3 cells PDGF BB Williams et al.(1984) CXCR2 (h) (IL-8B) human recombinant IL-8 White et al. (1998)(HEK-293 cells) TNF-α (h) U-937 cells TNF-α Brockhaus et al. (1990) CCR1(h) human recombinant MIP-1α Neote et al. (1993) (HEK-293 cells) H₁ (h)human recombinant pyrilamine Smit et al. (1996) (HEK-293 cells) H₂ (h)human recombinant cimetidine Leurs et al. (1994) (CHO cells) MC₄ (h)human recombinant NDP-α-MSH Schioth et al. (1997) (CHO cells) MT₁ (h)human recombinant melatonin Witt-Enderby and Dubocovich (CHO cells)(1996) M₁ (h) human recombinant pirenzepine Dorje et al. (1991) (CHOcells) M₂ (h) human recombinant methoctramine Dorje et al. (1991) (CHOcells) M₃ (h) human recombinant 4-DAMP Peralta et al. (1987) (CHO cells)M₄ (h) human recombinant 4-DAMP Dorje et al. (1991) (CHO cells) M₅ (h)human recombinant 4-DAMP Dorje et al. (1991) (CHO cells) NK₁ (h) U-373MGcells [Sar⁹,Met(O₂)¹¹]-SP Heuillet et al. (1993) NK₂ (h) humanrecombinant [Nle¹⁰]-NKA(4-10) Aharony et al. (1993) (CHO cells) NK₃ (h)human recombinant SB 222200 Sarau et al. (1997) (CHO cells) Y₁ (h)SK-N-MC cells NPY Wieland et al. (1995) Y₂ (h) KAN-TS cells NPYFuhlendorff et al. (1990) NT₁ (h) (NTS1) human recombinant neurotensinVita et al. (1993) (CHO cells) δ₂ (h) (DOP) human recombinant DPDPESimonin et al. (1994) (CHO cells) κ (KOP) guinea-pig U 50488 Kinouchiand Pasternak (1991) cerebellum μ (h) (MOP) (agonist site) humanrecombinant DAMGO Wang et al. (1994) (HEK-293 cells) ORL1 (h) (NOP)human recombinant nociceptin Ardati et al. (1997) (HEK-293 cells) PACAP(PAC₁) (h) human recombinant PACAP₁₋₃₈ Ohtaki et al. (1998) (CHO cells)PCP rat cerebral cortex MK 801 Vignon et al. (1986) TXA₂/PGH₂ (h) (TP)human platelets U 44069 Hedberg et al. (1988) P2X rat urinary bladderα,β-MeATP Bo and Burnstock (1990) P2Y rat cerebral cortex dATPαS Simonet al. (1995) 5-HT_(1A) (h) human recombinant 8-OH-DPAT Mulheron et al.(1994) (HEK-293 cells) 5-HT_(1B) rat cerebral cortex serotonin Hoyer etal. (1985) 5-HT_(2A) (h) human recombinant ketanserin Bonhaus et al.(1995) (HEK-293 cells) 5-HT_(2C) (h) human recombinant RS-102221 Stam etal. (1994) (CHO cells) 5-HT₃ (h) human recombinant MDL 72222 Hope et al.(1996) (CHO cells) 5-HT_(5A) (h) human recombinant serotonin Rees et al.(1994) (CHO cells) 5-HT₆ (h) human recombinant serotonin Monsma et al.(1993) (CHO cells) 5-HT₇ (h) human recombinant serotonin Shen et al.(1993) (CHO cells) σ (non-selective) rat cerebral cortex haloperidolShirayama et al. (1993) sst (non-selective) AtT-20 cells somatostatinBrown et al. (1990) VIP₁ (h) (VPAC₁) human recombinant VIP Couvineau etal. (1985) (CHO cells) V_(1a) (h) human recombinant [d(CH₂)₅¹,Tyr(Me)₂]-AVP Tahara et al. (1998) (CHO cells) Ca²⁺ channel (L,verapamil site) rat cerebral cortex D600 Reynolds et al. (1986)(phenylalkylamines) K⁺ _(V) channel rat cerebral cortex α-dendrotoxinSorensen and Blaustein (1989) SK⁺ _(Ca) channel rat cerebral cortexapamin Hugues et al. (1982) Na⁺ channel (site 2) rat cerebral cortexveratridine Brown (1986) Cl⁻ channel rat cerebral cortex picrotoxininLewin et al. (1989) NE transporter (h) human recombinant protriptylinePacholczyk et al. (1991) (CHO cells) DA transporter (h) humanrecombinant BTCP Pristupa et al. (1994) (CHO cells) 5-HT transporter (h)human recombinant imipramine Tatsumi et al. (1999) (CHO cells)

TABLE 2-A Non-Peptide Receptors Class Family Receptor Non-PeptideAdenosine A₁ A_(2A) A₃ Adrenergic α₁ α₂ β₁ β₂ Benzodiazepine BZD(central) BZD (peripheral) Cannabinoid CB₁ Dopamine D₁ D_(2S) D₃ D_(4.4)D₅ γ-aminobutyric acid GABA (non-selective) Histamine H₁ H₂ MelatoninMT₁ Muscarinic M₁ M₂ M₃ M₄ M₅ Glutamate PCP Prostanoid TXA₂/PGH₂Purinergic P2X P2Y Serotonin 5-HT_(1A) 5-HT_(1B) 5-HT_(2A) 5-HT_(2C)5-HT₃ 5-HT_(5A) 5-HT₆ 5-HT₇ Sigma σ (non-selective) Somatostatin sst(non-selective)

TABLE 2-B Peptide Receptors Class Family Receptor Peptide AngiotensinAT1 AT2 Bombesin BB Bradykinin B2 Calcitonin gene-related peptide CGRPCholecystokinin CCK_(A) (CCK₁) CCK_(B) (CCK₂) Endothelin ET_(A) ET_(B)Galanin GAL1 GAL2 Platelet-derived growth factor PDGF Chemokine ReceptorCXCR2 CCR1 Cytokine TNFα Melanocortin MC₄ Neurokinin NK₁ NK₂ NK₃Neuropeptide Y Y₁ Y₂ Neurotensin NT₁ Opioid & opioid-like δ₂ κ μ ORL1Vasoactive intestinal peptide PACAP VIP₁ Vasopressin V_(1a)

TABLE 2-C Ion Channels Class Family Receptor Ion Channel Calcium Ca²⁺(L, verapamil site) Potassium K⁺V SK⁺ _(Ca) Sodium Na⁺ (site 2) ChlorideCl⁻

TABLE 2-D Amine Transporters Class Family Receptor TransporterNorepinephrine NE transporter Dopamine DA transporter Serotonin 5-HTtransporter

TABLE 3 Method of Assay Ligand Conc. Non Specific Incubation DetectionA₁ (h) [³H]DPCPX 1 nM DPCPX 60 min./22° C. Scintillation (1 μM) countingA_(2A) (h) [³H]CGS 21680 6 nM NECA 120 min./22° C.  Scintillation (10μM) counting A₃ (h) [¹²⁵I]AB-MECA 0.15 nM IB-MECA 120 min./22° C. Scintillation (1 μM) counting α₁ (non-selective) [³H]prazosin 0.25 nMprazosin 60 min./22° C. Scintillation (0.5 μM) counting α₂(non-selective) [³H]RX 821002 0.5 nM (−)epinephrine 60 min./22° C.Scintillation (100 μM) counting β₁ (h) [³H](−)CGP 12177 0.15 nMalprenolol 60 min./22° C. Scintillation (50 μM) counting β₂ (h)[³H](−)CGP 12177 0.15 nM alprenolol 60 min./22° C. Scintillation (50 μM)counting AT₁ (h) [¹²⁵I][Sar¹,Ile⁸]-ATII 0.05 nM angiotensin II 60min./37° C. Scintillation (10 μM) counting AT₂ (h) [¹²⁵I]CGP 42112A 0.05nM angiotensin II 180 min./37° C.  Scintillation (1 μM) counting BZD(central) [³H]flunitrazepam 0.4 nM diazepam 60 min./4° C.  Scintillation(3 μM) counting BZD (peripheral) [³H]PK 11195 0.2 nM PK 11195 15min./22° C. Scintillation (10 μM) counting BB (non-selective)[¹²⁵I][Tyr⁴]bombesin 0.01 nM bombesin 60 min./22° C. Scintillation (1μM) counting B₂ (h) [³H]bradykinin 0.2 nM bradykinin 60 min./22° C.Scintillation (1 μM) counting CGRP (h) [¹²⁵I]hCGRPα 0.03 nM hCGRPα 90min./22° C. Scintillation (1 μM) counting CB₁ (h) [³H]CP 55940 0.5 nMWIN 55212-2 120 min./37° C.  Scintillation (10 μM) counting CCK_(A) (h)(CCK₁) [¹²⁵I]CCK-8 0.08 nM CCK-8 60 min./22° C. Scintillation (1 μM)counting CCK_(B) (h) (CCK₂) [¹²⁵I]CCK-8 0.04 nM CCK-8 60 min./22° C.Scintillation (1 μM) counting D₁ (h) [³H]SCH 23390 0.3 nM SCH 23390 60min./22° C. Scintillation (1 μM) counting D_(2S) (h) [³H]spiperone 0.3nM (+)butaclamol 60 min./22° C. Scintillation (10 μM) counting D₃ (h)[³H]spiperone 0.3 nM (+)butaclamol 60 min./22° C. Scintillation (10 μM)counting D_(4.4) (h) [³H]spiperone 0.3 nM (+)butaclamol 60 min./22° C.Scintillation (10 μM) counting D₅ (h) [³H]SCH 23390 0.3 nM SCH 23390 60min./22° C. Scintillation (10 μM) counting ET_(A) (h) [¹²⁵I]endothelin-10.03 nM endothelin-1 120 min./37° C.  Scintillation (0.1 μM) countingET_(B) (h) [¹²⁵I]endothelin-1 0.03 nM endothelin-1 120 min./37° C. Scintillation (0.1 μM) counting GABA (non-selective) [³H]GABA 10 nM GABA60 min./22° C. Scintillation (100 μM) counting GAL1 (h) [¹²⁵I]galanin0.1 nM galanin 60 min./22° C. Scintillation (1 μM) counting GAL2 (h)[¹²⁵I]galanin 0.05 nM galanin 120 min./22° C.  Scintillation (1 μM)counting PDGF [¹²⁵I]PDGF BB 0.03 nM PDGF BB 180 min./4° C. Scintillation (10 nM) counting CXCR2 (h) (IL-8B) [¹²⁵I]IL-8 0.025 nMIL-8 60 min./22° C. Scintillation (0.3 μM) counting TNF-α (h)[¹²⁵I]TNF-α 0.1 nM TNF-α 120 min./4° C.  Scintillation (10 nM) countingCCR1 (h) [¹²⁵I]MIP-1α 0.03 nM MIP-1α 120 min./22° C.  Scintillation (0.1μM) counting H₁ (h) [³H]pyrilamine 3 nM pyrilamine 60 min./22° C.Scintillation (1 μM) counting H₂ (h) [¹²⁵I]APT 0.2 nM tiotidine 120min./22° C.  Scintillation (100 μM) counting MC₄ (h) [¹²⁵I]NDP-α-MSH0.05 nM NDP-α-MSH 120 min./37° C.  Scintillation (1 μM) counting MT₁ (h)[¹²⁵I]iodomelatonin 0.025 nM melatonin 60 min./22° C. Scintillation (1μM) counting M₁ (h) [³H]pirenzepine 2 nM atropine 60 min./22° C.Scintillation (1 μM) counting M₂ (h) [³H]AF-DX 384 2 nM atropine 60min./22° C. Scintillation (1 μM) counting M₃ (h) [³H]4-DAMP 0.2 nMatropine 60 min./22° C. Scintillation (1 μM) counting M₄ (h) [³H]4-DAMP0.2 nM atropine 60 min./22° C. Scintillation (1 μM) counting M₅ (h)[³H]4-DAMP 0.3 nM atropine 60 min./22° C. Scintillation (1 μM) countingNK₁ (h) [¹²⁵I]BH-SP 0.15 nM [Sar⁹,Met(O₂)¹¹]-SP 60 min./22° C.Scintillation (1 μM) counting NK₂ (h) [¹²⁵I]NKA 0.1 nM [Nle¹⁰]-NKA(4-10)60 min./22° C. Scintillation (10 μM) counting NK₃ (h) [³H]SR 142801 0.4nM SB 222200 120 min./22° C.  Scintillation (10 μM) counting Y₁ (h)[¹²⁵I]peptide YY 0.025 nM NPY 120 min./37° C.  Scintillation (1 μM)counting Y₂ (h) [¹²⁵I]peptide YY 0.015 nM NPY 60 min./37° C.Scintillation (1 μM) counting NT₁ (h) (NTS1) [¹²⁵I]Tyr³-neurotensin 0.05nM neurotensin 60 min./4° C.  Scintillation (1 μM) counting δ₂ (h) (DOP)[³H]DADLE 0.5 nM naltrexone 120 min./22° C.  Scintillation (10 μM)counting κ (KOP) [³H]U 69593 0.7 nM naloxone 80 min./22° C.Scintillation (10 μM) counting μ (h) (MOP) (agonist site) [³H]DAMGO 0.5nM naloxone 120 min./22° C.  Scintillation (10 μM) counting ORL1 (h)(NOP) [³H]nociceptin 0.2 nM nociceptin 60 min./22° C. Scintillation (1μM) counting PACAP (PAC₁) (h) [¹²⁵I]PACAP₁₋₂₇ 0.015 nM PACAP₁₋₂₇ 120min./22° C.  Scintillation (0.1 μM) counting PCP [³H]TCP 5 nM MK 801 60min./22° C. Scintillation (10 μM) counting TXA₂/PGH₂ (h) (TP) [³H]SQ29548 5 nM U 44069 60 min./22° C. Scintillation (50 nM) counting P2X[³H]α,β-MeATP 3 nM α,β-MeATP 120 min./4° C.  Scintillation (10 μM)counting P2Y [³⁵S]dATPαS 10 nM dATPαS 60 min./22° C. Scintillation (10μM) counting 5-HT_(1A) (h) [³H]8-OH-DPAT 0.3 nM 8-OH-DPAT 60 min./22° C.Scintillation (10 μM) counting 5-HT_(1B) [¹²⁵I]CYP (+30 μM 0.1 nMserotonin 120 min./37° C.  Scintillation (−)propranolol) (10 μM)counting 5-HT_(2A) (h) [³H]ketanserin 0.5 nM ketanserin 60 min./22° C.Scintillation (1 μM) counting 5-HT_(2C) (h) [³H]mesulergine 1 nMRS-102221 60 min./37° C. Scintillation (10 μM) counting 5-HT₃ (h)[³H]BRL 43694 0.5 nM MDL 72222 120 min./22° C.  Scintillation (10 μM)counting 5-HT_(5A) (h) [³H]LSD 1 nM serotonin 60 min./37° C.Scintillation (100 μM) counting 5-HT₆ (h) [³H]LSD 2 nM serotonin 120min./37° C.  Scintillation (100 μM) counting 5-HT₇ (h) [³H]LSD 4 nMserotonin 120 min./22° C.  Scintillation (10 μM) counting σ(non-selective) [³H]DTG 8 nM haloperidol 120 min./22° C.  Scintillation(10 μM) counting sst (non-selective) [¹²⁵I]Tyr¹¹-somatostatin 0.05 nMsomatostatin 60 min./37° C. Scintillation (0.3 μM) counting VIP₁ (h)(VPAC₁) [¹²⁵I]VIP 0.04 nM VIP 60 min./22° C. Scintillation (0.3 μM)counting V_(1a) (h) [³H]AVP 0.3 nM AVP 60 min./22° C. Scintillation (1μM) counting Ca²⁺ channel (L, verapamil [³H](−)D 888 3 nM D 600 120min./22° C.  Scintillation site) (phenylalkyl amines) (10 μM) countingK⁺ _(V) channel [¹²⁵I]α-dendrotoxin 0.01 nM α-dendrotoxin 60 min./22° C.Scintillation (50 μM) counting SK⁺ _(Ca) channel [¹²⁵I]apamin 0.007 nMapamin 60 min./4° C.  Scintillation (0.1 μM) counting Na⁺ channel (site2) [³H]batrachotoxinin 10 nM veratridine 60 min./22° C. Scintillation(300 μM) counting Cl⁻ channel [³⁵S]TBPS 3 nM picrotoxinin 120 min./22°C.  Scintillation (20 μM) counting NE transporter (h) [³H]nisoxetine 1nM desipramine 120 min./4° C.  Scintillation (1 μM) counting DAtransporter (h) [³H]BTCP 4 nM BTCP 120 min./4° C.  Scintillation (10 μM)counting 5-HT transporter (h) [³H]imipramine 2 nM imipramine 60 min./22°C. Scintillation (10 μM) counting

For Table 4 below, the specific ligand binding to the receptors isdefined as the difference between the total binding and the nonspecificbinding determined in the presence of an excess of unlabelled ligand.The results are expressed as a percent inhibition of control specificbinding obtained in the presence of Compound I-1-Z. The IC₅₀ values(concentration causing a half-maximal inhibition of control specificbinding) and Hill coefficients (n_(H)) were determined by non-linearregression analysis of the competition curves using Hill equation curvefitting. The inhibition constants (K_(i)) were calculated from the ChengPrusoff equation (K_(i)=IC₅₀/(1+(L/K_(D))), where L=concentration ofradioligand in the assay, and K_(D)=affinity of the radioligand for thereceptor). In each experiment, the respective reference compound wastested concurrently with Compound I-1-Z in order to assess the assaysuitability. The reference compounds were tested at severalconcentrations to confirm that their IC₅₀ values were comparable withhistorical values, in order to confirm the validity of the assay (datanot shown).

The threshold for significance of the effect of the test compound (i.e.,the threshold for a true positive for receptor interaction) is taken asgreater than or equal to about 30% here, although other thresholds canbe used (such as greater than or equal to about 15%, or greater than orequal to about 20%, or greater than or equal to about 25%). Low tomoderate negative values for inhibition have no real meaning and areattributable to variability of the signal around the control level.TABLE 4 Summary Results 10 uM Concentration of Compound I-1-Z ReceptorMean Value A₁ (h) −3 A_(2A) (h) 13 A₃ (h) 1 α₁ (non-selective) 8 α₂(non-selective) 23 β₁ (h) 5 β₂ (h) 6 AT₁ (h) 10 AT₂ (h) −19 BZD(central) 14 BZD (peripheral) −6 BB (non-selective) 21 B₂ (h) 1 CGRP (h)−7 CB₁ (h) 14 CCK_(A) (h) (CCK₁) −13 CCK_(B) (h) (CCK₂) −5 D₁ (h) −2D_(2S) (h) −4 D₃ (h) −2 D_(4.4) (h) 2 D₅ (h) −10 ET_(A) (h) 8 ET_(B) (h)−5 GABA (non-selective) −19 GAL1 (h) 0 GAL2 (h) 12 PDGF −14 CXCR2 (h)(IL-8B) −8 TNF-α (h) −6 CCR1 (h) 3 H₁ (h) 3 H₂ (h) 16 MC₄ (h) 8 MT₁ (h)0 M₁ (h) 28 M₂ (h) 3 M₃ (h) 16 M₄ (h) 22 M₅ (h) 27 NK₁ (h) −6 NK₂ (h) 3NK₃ (h) 1 Y₁ (h) −2 Y₂ (h) 11 NT₁ (h) (NTS1) −1 δ₂ (h) (DOP) 0 κ (KOP)−18 μ (h) (MOP) (agonist site) 14 ORL1 (h) (NOP) −9 PACAP (PAC₁) (h) 5PCP −12 TXA₂/PGH₂ (h) (TP) 4 P2X −2 P2Y −1 5-HT_(1A) (h) 34 5-HT_(1B) 165-HT_(2A) (h) −4 5-HT_(2C) (h) 21 5-HT₃ (h) 4 5-HT_(5A) (h) −3 5-HT₆ (h)1 5-HT₇ (h) 13 σ (non-selective) 24 sst (non-selective) −4 VIP₁ (h)(VPAC₁) −13 V_(1a) (h) 9 Ca²⁺ channel (L, verapamil site) 14(phenylalkylamines) K⁺ _(V) channel −5 SK⁺ _(Ca) channel 4 Na⁺ channel(site 2) 9 Cl⁻ channel −6 NE transporter (h) 68 DA transporter (h) 385-HT transporter (h) 47

The following references describe the receptors and assays used in thesescreens: Aharony, D., et al. (1993) Mol. Pharmacol., 44.-356-363; Aiyar,N., et al., (1996) J. Biol. Chem., 271: 11325-11329; Ardati, A., et al.,(1997) Mol. Pharmacol., 51: 816-824; Bergsma, D. J., et al. (1992)Biochem. Biophys. Res. Commun., 183. 989-995; Bignon, E., et al. (1999)J. Pharmacol. Exp. Ther. 289: 742-751; Bloomquist, B. T. et al. (1998)Biochem. Biophys. Res. Commun., 243: 474-479; Bo, X. and Burnstock, G.(1990); Brit. J. Pharmacol., 101: 291-296; Bonhaus, D. W., et al. (1995)Brit. J. Pharmacol., 115: 622-628; Brockhaus, M., et al. (1990) Proc.Natl. Acad. Sci. U.S.A., 87: 3127-3131; Brown, G. B. (1986) J.Neurosci., 6: 2064-2070; Brown, P. J., et al. (1990) J. Biol. Chem.,265: 17995-18004; Buchan, K. W., et al. (1994) Brit. J. Pharmacol., 112:1251-1257, Couvineau, A., et al. (1985) Biochem. J., 231: 139-143;Dorje, F., et al. (1991) J. Pharmacol. Exp. Ther., 256: 727-733; Fuchs,S., et al. (2001) Mol. Med., 7: 115-124; Fuhlendorff, J., et al. (1990)Proc. Natl. Acad. Sci. U.S.A., 87: 182-186; Grandy, D. K., et al. (1989)Proc. Natl. Acad. Sci. US.A., 86: 9762-9766; Greengrass, P. and Bremner,R. (1979) Eur. J. Pharmacol., 55: 323-326; Guard, S., et al. (1993) Eur.J. Pharmacol., 240: 177-184; Hedberg, A., et al. (1988) J. Pharmacol.Exp. Ther., 245: 786-792; Heuillet, E., et al. (1993) J. Neurochem., 60:868-876,; Hope, A. G., et al. (1996) Brit. J. Pharmacol., 118:1237-1245; Hoyer, D., et al. (1985) Eur. J. Pharmacol., 118: 1-12;Hugues, M., et al. (1982) J. Biol. Chem., 257: 2762-2769; Kinouchi, K.and Pasternak, G. W. (1991) Eur. J. Pharmacol., 2077: 135-141; Le Fur,G., et al. (1983) Life Sci., 33: 449-457, Lee, Y.-M., et al. (1993) J.Biol. Chem., 268: 8164-8169; Leurs, R., et al. (1994) Brit. J.Pharmacol., 112: 847-854; Levin, M. C., et al. (2002) J. Biol.Chem.,277: 30429-30435; Lewin, A. H., et al. (1989) Mol. Pharmacol., 35:189-194; Luthin, D. R., et al. (1995) Mol. Pharmacol., 47: 307-313;Mackenzie, R. G., et al. (1994) Eur. J. Pharmacol., 266: 79-85; Monsma,F. J., et al. (1993) Mol. Pharmacol., 43: 320-3277; Mulheron, J. G., etal. (1994) J. Biol. Chem., 269: 12954-12962; Neote,. K., et al. (1993)Cell, 72: 415-425; Ohtaki, T., et al. (1998) J. Biol. Chem., 273:15464-15473; Pacholczyk, T., et al. (1991) Nature, 350: 350-354;Peralta, E. G., et al. (1987) EMBO. J., 6: 3923-3929; Pristupa, Z. B.,et al. (1994) Mol. Pharmacol., 45: 125-135; Pruneau, D., et al. (1998)Brit. J. Pharmacol., 125: 365-372; Rees, S., et al. (1994) FEBS Lett.,355: 242-246; Reynolds, I. J., et al. (1986) J. Pharmacol. Exp. Ther.,2377: 731-738; Rinaldi-Carmona, M., et al. (1996) J. Pharmacol. Exp.Ther., 278: 871-878; Salvatore, C. A., et al. (1993) Proc. Natl. Acad.Sci. US.A., 90: 10365-10369; Sarau, H. M., et al. (1997) J. Pharmacol.Exp. Ther., 281: 1303-1311; Schioth, H. B., et al. (1997) Neuropeptides,31: 565-571; Shen, Y., et al. (1993) J. Biol. Chem., 268: 18200-18204;Shirayama, Y., et al. (1993) Eur. J. Pharmacol., 237; 117-126; Simon,J., et al. (1995) Pharmacol. Toxicol., 76: 302-307; Simonin, F., et al.(1994) Mol. Pharmacol., 46: 1015-1021; Smit, M. J., et al. (1996) Brit.J. Pharmacol., 1177: 1071-1080; Smith, C. and Teitler, M. (1999)Cardiovasc. Drugs Ther., 13: 123-126,; Sorensen, R. G. and Blaustein, M.P. (1989) Mol. Pharmacol., 36: 689-698; Speth, R. C., et al. (1979) LifeSci., 24: 351-358; Stam, N. J., et al. (1994) Eur. J. Pharmacol., 269:339-348; Sullivan, K. A., et al. (1997) Biochem. Biophys. Res. Commun.,233: 823-828; Sunahara, R. K., et al. (1991) Nature, 350: 614-619;Tahara, A., et al. (1998) Brit. J. Pharmacol., 125: 1463-1470; Tatsumi,M., et al. (1999) Eur. J. Pharmacol., 368: 277-283; Townsend-Nicholson,A. and Schofield, P. R. (1994) J. Biol. Chem., 269: 2373-2376; Tsuji,A., et al. (1988) Antimicrob. Agents Chemother., 32: 190-194; Tsuzuki,S., et al. (1994) Biochem. Biophys. Res. Commun., 200: 1449-1454; Uhlen,S. and Wikberg, J. E. (1991) Pharmacol. Toxicol., 69: 341-350; Van Tol,H. H. M., et al. (1992) Nature, 358: 149-152; Vignon, J., et al. (1986)Brain Res., 378: 133-141; Vita, N., et al. (1993) FEBS Lett., 317:139-142; Wang, J.-B., et al. (1994) FEBS Lett., 338: 217-222; White, J.R., et al. (1998) J. Biol. Chem., 273: 10095-10098; Wieland, H. A., etal. (1995) J. Pharmacol. Exp. Ther., 275: 143-149; Williams, L. T., etal. (1984) J. Biol. Chem., 259: 5287-5294; Witt-Enderby, P. A. andDubocovich, M. L. (1996) Mol. Pharmacol., 50: 166-174; Zhou, Q.-Y., etal. (1990) Nature, 347: 76-80.

The disclosures of all publications, patents, patent applications andpublished patent applications referred to herein by an identifyingcitation are hereby incorporated herein by reference in their entirety.

Although the foregoing invention has been described in some detail byway of illustration and example for purposes of clarity ofunderstanding, it is apparent to those skilled in the art that certainminor changes and modifications will be practiced. Therefore, thedescription and examples should not be construed as limiting the scopeof the invention.

1. A method of treating or preventing inflammation, an inflammatorydisease, an immune disease, or an autoimmune disease, comprisingadministering a therapeutically effective amount of a compound of theformula:

wherein Y is aryl or heteroaryl optionally substituted with one or moregroups of the form R₁, wherein each R₁ is independently selected fromC₁-C₈ alkyl, C₃-C₈ cycloalkyl, —O—C₁-C₈ alkyl, —O—C₃-C₈ cycloalkyl,—C₆-C₁₀ aryl, —O—C₁-C₄ alkyl-C₆-C₁₀ aryl, —S—C₁-C₈ alkyl, —CF₃, —S—CF₃,—OCF₃, —OCH₂CF₃, F, Cl, Br, I, —NO₂, —OH, —CN, —NR₅R₆, —NHR₇, and—S(O₂)—(C₁-C₈ alkyl); R₂ is selected from H, F, Cl, C₁-C₄ alkyl, and—CF₃; R₃ and R₄ are independently selected from H, —C₁-C₈ alkyl, —C₁-C₄alkyl-C₆-C₁₀ aryl, or R₃ and R₄ together with the nitrogen to which theyare attached form a nitrogen-containing ring; R₅ and R₆ areindependently selected from H, -CI-C₈ alkyl, —C₁-C₄ alkyl-C₆-C₁₀ aryl,or R₅ and R₆ together with the nitrogen to which they are attached forma nitrogen-containing ring; R₇ is selected from —C(═O)—(C₁-C₈ alkyl) and—C(═O)—(C₆-C₁₀ aryl); X is —CH₂—, —O—, or —S—; n is 0, 1, 2, or 3; andany stereoisomer, mixture of stereoisomers, prodrug, metabolite,crystalline form, non-crystalline form, hydrate, solvate, or saltthereof.
 2. The method of claim 1, wherein X is CH₂ and n is
 0. 3. Themethod of claim 1, wherein X is CH₂ and n is
 1. 4. The method of claim1, wherein Y is phenyl, optionally substituted with one or more groupsof the form R₁.
 5. The method of claim 1, wherein R₃ and R₄ are both H.6. The method of claim 1, wherein the double bond is in the Zconfiguration.
 7. The method of claim 1, wherein the double bond is inthe E configuration.
 8. The method of claim 1, wherein R₂ is F.
 9. Themethod of claim 1, wherein R₂ is Cl.
 10. The method of claim 1, whereinX is O and n is
 0. 11. The method of claim 1, wherein the inflammationor inflammatory disease or immune or autoimmune disease is multiplesclerosis, chronic multiple sclerosis, synovitis, systemic inflammatorysepsis, inflammatory bowel diseases, Crohn's disease, ulcerativecolitis, Alzheimer's disease, vascular dementia, atherosclerosis,rheumatoid arthritis, juvenile rheumatoid arthritis, pulmonaryinflammation, asthma, skin inflammation, contact dermatitis, liverinflammation, liver autoimmune diseases, autoimmune hepatitis, primarybiliary cirrhosis, sclerosing cholangitis, autoimmune cholangitis,alcoholic liver disease, Type I diabetes and/or complications thereof,Type II diabetes and/or complications thereof, atherosclerosis, chronicheart failure, congestive heart failure, ischemic diseases, strokeand/or complications thereof, or myocardial infarction and/orcomplications thereof.
 12. The method of claim 11, wherein theinflammation or inflammatory disease or immune or autoimmune disease ismultiple sclerosis, chronic multiple sclerosis, stroke, or complicationsof stroke.
 13. The method of claim 1, wherein the compound is:(Z)-2-(4-ethoxybenzyl)-3-fluoroprop-2-en-1-amine,(Z)-2-(4-chlorobenzyl)-3-fluoroprop-2-en-1-amine,(Z)-2-(3-chlorobenzyl)-3-fluoroprop-2-en-1-amine,(Z)-3-fluoro-2-(4-isopropoxybenzyl)prop-2-en-1-amine,(Z)-3-fluoro-2-(4-(methylthio)benzyl)prop-2-en-1-amine,(Z)-3-fluoro-2-(3-(methylthio)benzyl)prop-2-en-1-amine,(Z)-3-fluoro-2-(4-(methylsulfonyl)benzyl)prop-2-en-1-amine,(Z)-3-fluoro-2-(4-methylbenzyl)prop-2-en-1-amine,(Z)-3-fluoro-2-(3-methylbenzyl)prop-2-en-1-amine,(Z)-3-fluoro-2-(4-isopropylbenzyl)prop-2-en-1-amine,(Z)-2-(4-tert-butylbenzyl)-3-fluoroprop-2-en-1-amine,(Z)-2-(biphenyl-4-ylmethyl)-3-fluoroprop-2-en-1-amine,(Z)-3-fluoro-2-(4-fluorobenzyl)prop-2-en-1-amine,(Z)-3-fluoro-2-(3-(trifluoromethyl)benzyl)prop-2-en-1-amine,(Z)-3-fluoro-2-(3-fluorobenzyl)prop-2-en-1-amine,(Z)-3-fluoro-2-(3-fluoro-4-methylbenzyl)prop-2-en-1-amine,(Z)-3-fluoro-2-(3-fluoro-4-methoxybenzyl)prop-2-en-1-amine,(Z)-3-fluoro-2-(4-fluoro-3-methylbenzyl)prop-2-en-1-amine,(Z)-2-(3-chloro-4-fluorobenzyl)-3-fluoroprop-2-en-1-amine,(Z)-2-(2,5-difluorobenzyl)-3-fluoroprop-2-en-1-amine,(Z)-2-(3-chloro-5-fluorobenzyl)-3-fluoroprop-2-en-1-amine,(Z)-2-(2,4-difluorobenzyl)-3-fluoroprop-2-en-1-amine,(Z)-2-(3,5-dichlorobenzyl)-3-fluoroprop-2-en-1-amine,(Z)-2-(3,4-difluorobenzyl)-3-fluoroprop-2-en-1-amine,(Z)-2-(chloromethylene)-4-(4-fluorophenyl)butan-1-amine,(Z)-2-(chloromethylene)-4-(4-chlorophenyl)butan-1-amine,(Z)-2-(chloromethylene)-4-(4-methoxyphenyl)butan-1-amine,(Z)-2-(chloromethylene)-4-(4-ethoxyphenyl)butan-1-amine,(Z)-2-(chloromethylene)-4-(4-(trifluoromethyl)phenyl)butan-1-amine,(Z)-4-(4-butoxyphenyl)-2-(chloromethylene)butan-1-amine,(Z)-2-(chloromethylene)-4-m-tolylbutan-1-amine,(Z)-2-(chloromethylene)-4-(3-methoxyphenyl)butan-1-amine,(Z)-2-(chloromethylene)-4-p-tolylbutan-1-amine,(Z)-2-(chloromethylene)-4-(3-fluoro-5-(trifluoromethyl)phenyl)butan-1-amine,(Z)-2-(chloromethylene)-4-(4-fluorophenyl)butan-1-amine,(Z)-2-(chloromethylene)-4-(4-chlorophenyl)butan-1-amine,(Z)-2-(chloromethylene)-4-(4-methoxyphenyl)butan-1-amine,(Z)-2-(chloromethylene)-4-(4-ethoxyphenyl)butan-1-amine,(Z)-2-(chloromethylene)-4-(4-(trifluoromethyl)phenyl)butan-1-amine,(Z)-4-(4-butoxyphenyl)-2-(chloromethylene)butan-1-amine,(Z)-2-(chloromethylene)-4-m-tolylbutan-1-amine,(Z)-2-(chloromethylene)-4-(3-methoxyphenyl)butan-1-amine,(Z)-2-(chloromethylene)-4-p-tolylbutan-1-amine,(Z)-2-(chloromethylene)-4-(3-fluoro-5-(trifluoromethyl)phenyl)butan-1-amine,(Z)-2-(4-(cyclopropylmethoxy)benzyl)-3-fluoroprop-2-en-1-amine,(Z)-2-(4-(cyclopropylmethoxy)-3-fluorobenzyl)-3-fluoroprop-2-en-1-amine,(Z)-3-fluoro-2-(3-fluoro-4-(pentyloxy)benzyl)prop-2-en-1-amine,(Z)-3-fluoro-2-(2,3,5,6-tetrafluoro-4-methoxybenzyl)prop-2-en-1-amine,(Z)-2-(4-ethoxy-3-fluorobenzyl)-3-fluoroprop-2-en-1-amine,(Z)-2-(2,3-difluoro-4-methoxybenzyl)-3-fluoroprop-2-en-1-amine,(Z)-2-(4-(benzyloxy)-3-fluorobenzyl)-3-fluoroprop-2-en-1-amine,(Z)-3-fluoro-2-(4-fluoro-3-(trifluoromethoxy)benzyl)prop-2-en-1-amine,(Z)-3-fluoro-2-(4-(2,2,2-trifluoroethoxy)benzyl)prop-2-en-1-amine,(Z)-2-(3,5-difluoro-4-methoxybenzyl)-3-fluoroprop-2-en-1-amine,(Z)-2-(3-ethoxybenzyl)-3-fluoroprop-2-en-1-amine,(Z)-3-fluoro-2-(3-isopropoxybenzyl)prop-2-en-1-amine,(Z)-3-fluoro-2-(3-(trifluoromethoxy)benzyl)prop-2-en-1-amine,(Z)-2-(3-(cyclopropylmethoxy)benzyl)-3-fluoroprop-2-en-1-amine,(Z)-2-(3-(benzyloxy)benzyl)-3-fluoroprop-2-en-1-amine,(Z)-3-fluoro-2-(2-fluoro-5-(trifluoromethoxy)benzyl)prop-2-en-1-amine,(Z)-2-(3-chloro-5-(trifluoromethoxy)benzyl)-3-fluoroprop-2-en-1-amine,(Z)-3-fluoro-2-(2,3,5-trifluorobenzyl)prop-2-en-1-amine,(Z)-3-fluoro-2-(3,4,5-trifluorobenzyl)prop-2-en-1-amine,(Z)-3-(2-(aminomethyl)-3-fluoroallyl)benzonitrile,(Z)-2-(4-bromobenzyl)-3-fluoroprop-2-en-1-amine,(Z)-2-(3-bromobenzyl)-3-fluoroprop-2-en-1-amine,(Z)-3-fluoro-2-(pyridin-2-ylmethyl)prop-2-en-1-amine,(Z)-3-fluoro-2-(pyridin-3-ylmethyl)prop-2-en-1-amine,(Z)-3-fluoro-2-(naphthalen-2-ylmethyl)prop-2-en-1-amine,(Z)-2-(benzofuran-2-ylmethyl)-3-fluoroprop-2-en-1-amine,(Z)-2-(benzofuran-3-ylmethyl)-3-fluoroprop-2-en-1-amine,(Z)-3-fluoro-2-(quinolin-3-ylmethyl)prop-2-en-1-amine,(Z)-2-(benzo[b]thiophen-3-ylmethyl)-3-fluoroprop-2-en-1-amine,(Z)-2-(benzo[b]thiophen-2-ylmethyl)-3-fluoroprop-2-en-1-amine,(E)-2-((4-ethoxyphenoxy)methyl)-3-fluoroprop-2-en-1-amine,(E)-2-((4-butoxyphenoxy)methyl)-3-fluoroprop-2-en-1-amine,(E)-3-fluoro-2-(m-tolyloxymethyl)prop-2-en-1-amine,(E)-3-fluoro-2-(p-tolyloxymethyl)prop-2-en-1-amine,(E)-3-fluoro-2-((3-fluoro-5-(trifluoromethyl)phenoxy)methyl)prop-2-en-1-amine,(Z)-3-fluoro-2-(furan-2-ylmethyl)prop-2-en-1-amine,(Z)-3-fluoro-2-(thiophen-2-ylmethyl)prop-2-en-1-amine,(Z)-2-((5-chlorothiophen-2-yl)methyl)-3-fluoroprop-2-en-1-amine,(Z)-3-fluoro-2-((5-methylthiophen-2-yl)methyl)prop-2-en-1-amine,(Z)-3-fluoro-2-(furan-3-ylmethyl)prop-2-en-1-amine,(Z)-3-fluoro-2-(thiophen-3-ylmethyl)prop-2-en-1-amine,(Z)-2-((5-chlorothiophen-3-yl)methyl)-3-fluoroprop-2-en-1-amine,(Z)-2-(fluoromethylene)-4-(3-fluorophenyl)butan-1-amine,(Z)-4-(4-chlorophenyl)-2-(fluoromethylene)butan-1-amine,(Z)-2-(fluoromethylene)-4-(4-methoxyphenyl)butan-1-amine,(Z)-4-(4-ethoxyphenyl)-2-(fluoromethylene)butan-1-amine,(Z)-2-(fluoromethylene)-4-(4-(trifluoromethyl)phenyl)butan-1-amine,(Z)-4-(4-butoxyphenyl)-2-(fluoromethylene)butan-1-amine,(Z)-2-(fluoromethylene)-4-m-tolylbutan-1-amine,(Z)-2-(fluoromethylene)-4-(3-methoxyphenyl)butan-1-amine,(Z)-2-(fluoromethylene)-4-p-tolylbutan-1-amine,(Z)-4-(3-fluoro-5-(trifluoromethyl)phenyl)-2-(fluoromethylene)butan-1-amine,(E)-2-(4-ethoxybenzyl)-3-fluoroprop-2-en-1-amine,(E)-2-(4-chlorobenzyl)-3-fluoroprop-2-en-1-amine,(E)-2-(3-chlorobenzyl)-3-fluoroprop-2-en-1-amine,(E)-3-fluoro-2-(4-isopropoxybenzyl)prop-2-en-1-amine,(E)-3-fluoro-2-(4-(methylthio)benzyl)prop-2-en-1-amine,(E)-3-fluoro-2-(3-(methylthio)benzyl)prop-2-en-1-amine,(E)-3-fluoro-2-(4-(methylsulfonyl)benzyl)prop-2-en-1-amine,(E)-3-fluoro-2-(4-methylbenzyl)prop-2-en-1-amine,(E)-3-fluoro-2-(3-methylbenzyl)prop-2-en-1-amine,(E)-3-fluoro-2-(4-isopropylbenzyl)prop-2-en-1-amine,(E)-2-(4-tert-butylbenzyl)-3-fluoroprop-2-en-1-amine,(E)-2-(biphenyl-4-ylmethyl)-3-fluoroprop-2-en-1-amine,(E)-3-fluoro-2-(4-fluorobenzyl)prop-2-en-1-amine,(E)-3-fluoro-2-(3-(trifluoromethyl)benzyl)prop-2-en-1-amine,(E)-3-fluoro-2-(3-fluorobenzyl)prop-2-en-1-amine,(E)-3-fluoro-2-(3-fluoro-4-methylbenzyl)prop-2-en-1-amine,(E)-3-fluoro-2-(3-fluoro-4-methoxybenzyl)prop-2-en-1-amine,(E)-3-fluoro-2-(4-fluoro-3-methylbenzyl)prop-2-en-1-amine,(E)-2-(3-chloro-4-fluorobenzyl)-3-fluoroprop-2-en-1-amine,(E)-2-(2,5-difluorobenzyl)-3-fluoroprop-2-en-1-amine,(E)-2-(3-chloro-5-fluorobenzyl)-3-fluoroprop-2-en-1-amine,(E)-2-(2,4-difluorobenzyl)-3-fluoroprop-2-en-1-amine,(E)-2-(3,5-dichlorobenzyl)-3-fluoroprop-2-en-1-amine,(E)-2-(3,4-difluorobenzyl)-3-fluoroprop-2-en-1-amine,(E)-2-(chloromethylene)-4-(4-fluorophenyl)butan-1-amine,(E)-2-(chloromethylene)-4-(4-chlorophenyl)butan-1-amine,(E)-2-(chloromethylene)-4-(4-methoxyphenyl)butan-1-amine,(E)-2-(chloromethylene)-4-(4-ethoxyphenyl)butan-1-amine,(E)-2-(chloromethylene)-4-(4-(trifluoromethyl)phenyl)butan-1-amine,(E)-4-(4-butoxyphenyl)-2-(chloromethylene)butan-1-amine,(E)-2-(chloromethylene)-4-m-tolylbutan-1-amine,(E)-2-(chloromethylene)-4-(3-methoxyphenyl)butan-1-amine,(E)-2-(chloromethylene)-4-p-tolylbutan-1-amine,(E)-2-(chloromethylene)-4-(3-fluoro-5-(trifluoromethyl)phenyl)butan-1-amine,(E)-2-(chloromethylene)-4-(4-fluorophenyl)butan-1-amine,(E)-2-(chloromethylene)-4-(4-chlorophenyl)butan-1-amine,(E)-2-(chloromethylene)-4-(4-methoxyphenyl)butan-1-amine,(E)-2-(chloromethylene)-4-(4-ethoxyphenyl)butan-1-amine,(E)-2-(chloromethylene)-4-(4-(trifluoromethyl)phenyl)butan-1-amine,(E)-4-(4-butoxyphenyl)-2-(chloromethylene)butan-1-amine,(E)-2-(chloromethylene)-4-m-tolylbutan-1-amine,(E)-2-(chloromethylene)-4-(3-methoxyphenyl)butan-1-amine,(E)-2-(chloromethylene)-4-p-tolylbutan-1-amine,(E)-2-(chloromethylene)-4-(3-fluoro-5-(trifluoromethyl)phenyl)butan-1-amine,(E)-2-(4-(cyclopropylmethoxy)benzyl)-3-fluoroprop-2-en-1-amine,(E)-2-(4-(cyclopropylmethoxy)-3-fluorobenzyl)-3-fluoroprop-2-en-1-amine,(E)-3-fluoro-2-(3-fluoro-4-(pentyloxy)benzyl)prop-2-en-1-amine,(E)-3-fluoro-2-(2,3,5,6-tetrafluoro-4-methoxybenzyl)prop-2-en-1-amine,(E)-2-(4-ethoxy-3-fluorobenzyl)-3-fluoroprop-2-en-1-amine,(E)-2-(2,3-difluoro-4-methoxybenzyl)-3-fluoroprop-2-en-1-amine,(E)-2-(4-(benzyloxy)-3-fluorobenzyl)-3-fluoroprop-2-en-1-amine,(E)-3-fluoro-2-(4-fluoro-3-(trifluoromethoxy)benzyl)prop-2-en-1-amine,(E)-3-fluoro-2-(4-(2,2,2-trifluoroethoxy)benzyl)prop-2-en-1-amine,(E)-2-(3,5-difluoro-4-methoxybenzyl)-3-fluoroprop-2-en-1-amine,(E)-2-(3-ethoxybenzyl)-3-fluoroprop-2-en-1-amine,(E)-3-fluoro-2-(3-isopropoxybenzyl)prop-2-en-1-amine,(E)-3-fluoro-2-(3-(trifluoromethoxy)benzyl)prop-2-en-1-amine,(E)-2-(3-(cyclopropylmethoxy)benzyl)-3-fluoroprop-2-en-1-amine,(E)-2-(3-(benzyloxy)benzyl)-3-fluoroprop-2-en-1-amine,(E)-3-fluoro-2-(2-fluoro-5-(trifluoromethoxy)benzyl)prop-2-en-1-amine,(E)-2-(3-chloro-5-(trifluoromethoxy)benzyl)-3-fluoroprop-2-en-1-amine,(E)-3-fluoro-2-(2,3,5-trifluorobenzyl)prop-2-en-1-amine,(E)-3-fluoro-2-(3,4,5-trifluorobenzyl)prop-2-en-1-amine,(E)-3-(2-(aminomethyl)-3-fluoroallyl)benzonitrile,(E)-2-(4-bromobenzyl)-3-fluoroprop-2-en-1-amine,(E)-2-(3-bromobenzyl)-3-fluoroprop-2-en-1-amine,(E)-3-fluoro-2-(pyridin-2-ylmethyl)prop-2-en-1-amine,(E)-3-fluoro-2-(pyridin-3-ylmethyl)prop-2-en-1-amine,(E)-3-fluoro-2-(naphthalen-2-ylmethyl)prop-2-en-1-amine,(E)-2-(benzofuran-2-ylmethyl)-3-fluoroprop-2-en-1-amine,(E)-2-(benzofuran-3-ylmethyl)-3-fluoroprop-2-en-1-amine,(E)-3-fluoro-2-(quinolin-3-ylmethyl)prop-2-en-1-amine,(E)-2-(benzo[b]thiophen-3-ylmethyl)-3-fluoroprop-2-en-1-amine,(E)-2-(benzo[b]thiophen-2-ylmethyl)-3-fluoroprop-2-en-1-amine,(Z)-2-((4-ethoxyphenoxy)methyl)-3-fluoroprop-2-en-1-amine,(Z)-2-((4-butoxyphenoxy)methyl)-3-fluoroprop-2-en-1-amine,(Z)-3-fluoro-2-(m-tolyloxymethyl)prop-2-en-1-amine,(Z)-3-fluoro-2-(p-tolyloxymethyl)prop-2-en-1-amine,(Z)-3-fluoro-2-((3-fluoro-5-(trifluoromethyl)phenoxy)methyl)prop-2-en-1-amine,(E)-3-fluoro-2-(furan-2-ylmethyl)prop-2-en-1-amine,(E)-3-fluoro-2-(thiophen-2-ylmethyl)prop-2-en-1-amine,(E)-2-((5-chlorothiophen-2-yl)methyl)-3-fluoroprop-2-en-1-amine,(E)-3-fluoro-2-((5-methylthiophen-2-yl)methyl)prop-2-en-1-amine,(E)-3-fluoro-2-(furan-3-ylmethyl)prop-2-en-1-amine,(E)-3-fluoro-2-(thiophen-3-ylmethyl)prop-2-en-1-amine,(E)-2-((5-chlorothiophen-3-yl)methyl)-3-fluoroprop-2-en-1-amine,(E)-2-(fluoromethylene)-4-(3-fluorophenyl)butan-1-amine,(E)-4-(4-chlorophenyl)-2-(fluoromethylene)butan-1-amine,(E)-2-(fluoromethylene)-4-(4-methoxyphenyl)butan-1-amine,(E)-4-(4-ethoxyphenyl)-2-(fluoromethylene)butan-1-amine,(E)-2-(fluoromethylene)-4-(4-(trifluoromethyl)phenyl)butan-1-amine,(E)-4-(4-butoxyphenyl)-2-(fluoromethylene)butan-1-amine,(E)-2-(fluoromethylene)-4-m-tolylbutan-1-amine,(E)-2-(fluoromethylene)-4-(3-methoxyphenyl)butan-1-amine,(E)-2-(fluoromethylene)-4-p-tolylbutan-1-amine, or(E)-4-(3-fluoro-5-(trifluoromethyl)phenyl)-2-(fluoromethylene)butan-1-amine,or any stereoisomer, mixture of stereoisomers, prodrug, metabolite,crystalline form, non-crystalline form, hydrate, solvate, or saltthereof.
 14. The method of claim 1, wherein the compound is of theformula:

or any solvate, hydrate, crystalline form, non-crystalline form, or saltthereof, in a therapeutically effective amount.
 15. A method ofinhibiting SSAO activity in a subject, comprising administering(Z)-2-(4′-methoxybenzyl)-3-fluoroallylamine:

to the subject in an amount sufficient to inhibit SSAO activity by atleast about 75% while inhibiting MAO by no more than about 10%.
 16. Aunit dosage formulation of (Z)-2-(4′-methoxybenzyl)-3-fluoroallylamine:

wherein the dosage contains an amount sufficient to inhibit SSAOactivity by at least about 75% while inhibiting MAO by no more thanabout 10%.
 17. A method of treating or preventing inflammation or aninflammatory disease, immune or autoimmune disease, multiple sclerosisor chronic multiple sclerosis, or ischemic disease or the sequelae of anischemic disease, comprising administering a therapeutically effectiveamount of a compound of the formula:

wherein Y is a phenyl, naphthyl, or pyridyl group optionally substitutedwith one or more groups of the form R₁, wherein each R₁ is independentlyselected from H, C₁-C₈ alkyl, C₃-C₈ cycloalkyl, —O—C₁-C₈ alkyl, —O—C₃-C₈cycloalkyl, —C₆-C₁₀ aryl, —O—C₁-C₄ alkyl-C₆-C₁₀ aryl, —S—C₁-C₈ alkyl,—CF₃, —OCF₃, F, Cl, Br, I, —NO₂, —OH, —NR₅R₆, —NHR₇, and —S(O₂)—(C₁-C₈alkyl); R₂ is selected from H, F, Cl, C₁-C₄ alkyl, and CF₃; R₃ and R₄are independently selected from H, —C₁-C₈ alkyl, —C₁-C₄ alkyl-C₆-C₁₀aryl, or R₃ and R₄ together with the nitrogen to which they are attachedform a nitrogen-containing ring; R₅ and R₆ are independently selectedfrom H, —C₁-C₈ alkyl, —C₁-C₄ alkyl-C₆-C₁₀ aryl, or R₅ and R₆ togetherwith the nitrogen to which they are attached form a nitrogen-containingring; R₇ is selected from —C(═O)—(C₁-C₈ alkyl) and —C(═O)—(C₆-C₁₀ aryl);R₈ is selected from H, C₁-C₈ alkyl, C₆-C₁₀ aryl, —C₁-C₄ alkyl-C₆-C₁₀aryl, and —CF₃; X is —CH₂—, —O—, or —S—; n is 0, 1, 2, or 3; and p is 0,1, 2, or 3; and any stereoisomer, mixture of stereoisomers, prodrug,metabolite, crystalline form, non-crystalline form, hydrate, solvate, orsalt thereof.
 18. The method of claim 17, wherein X is CH₂ and n is 1.19. The method of claim 17, wherein X is CH₂ and n is
 0. 20. The methodof claim 17, wherein Y is phenyl, optionally substituted with one ormore groups of the form R₁.
 21. The method of claim 17, wherein R₃ andR₄ are both H.
 22. The method of claim 17, wherein X is O or S and nis
 1. 23. The method of claim 17, wherein the double bond is in the Econfiguration.
 24. The method of claim 17, wherein the double bond is inthe Z configuration.
 25. The method of claim 17, wherein the compoundis: (E)-2-fluoro-4-(3-fluoro-5-(trifluoromethyl)phenyl)but-2-en-1-amine,(E)-2-fluoro-4-(3-(trifluoromethyl)phenyl)but-2-en-1-amine,(E)-2-fluoro-4-(4-methoxyphenyl)but-2-en-1-amine,(E)-2-fluoro-4-(4-methoxy-3-(trifluoromethyl)phenyl)but-2-en-1-amine,(E)-2-fluoro-4-(4-fluorophenyl)but-2-en-1-amine,(E)-2-fluoro-4-m-tolylbut-2-en-1-amine,(E)-2-fluoro-4-(3-fluorophenyl)but-2-en-1-amine,(E)-2-fluoro-4-(3-methoxyphenyl)but-2-en-1-amine,(E)-2-fluoro-4-phenylbut-2-en-1-amine,(E)-2-fluoro-4-(3-(trifluoromethoxy)phenyl)but-2-en-1-amine,(E)-3-(4-amino-3-fluorobut-2-enyl)-N,N-dimethylbenzenamine,(E)-4-(3,5-bis(trifluoromethyl)phenyl)-2-fluorobut-2-en-1-amine,(E)-2-fluoro-4-(3-(methylthio)phenyl)but-2-en-1-amine,(E)-2-fluoro-4-(3-(methylsulfonyl)phenyl)but-2-en-1-amine,(E)-2-fluoro-4-(3-(trifluoromethylthio)phenyl)but-2-en-1-amine,(E)-2-fluoro-4-(3-(methoxymethyl)phenyl)but-2-en-1-amine,(E)-2-fluoro-4-(2-methoxyphenyl)but-2-en-1-amine,(E)-2-fluoro-4-(3-methoxyphenyl)-3-methylbut-2-en-1-amine,(E)-2-fluoro-4-(3-methoxyphenoxy)but-2-en-1-amine,(E)-2-fluoro-4-(3-methoxyphenylthio)but-2-en-1-amine,(E)-2-fluoro-4-(3-(trifluoromethyl)phenoxy)but-2-en-1-amine,(E)-2-fluoro-4-(pyridin-3-yloxy)but-2-en-1-amine,(E)-2-fluoro-5-(3-methoxyphenyl)pent-2-en-1-amine,(Z)-2-fluoro-4-(3-fluoro-5-(trifluoromethyl)phenyl)but-2-en-1-amine,(Z)-2-fluoro-4-(3-(trifluoromethyl)phenyl)but-2-en-1-amine,(Z)-2-fluoro-4-(4-methoxyphenyl)but-2-en-1-amine,(Z)-2-fluoro-4-(4-methoxy-3-(trifluoromethyl)phenyl)but-2-en-1-amine,(Z)-2-fluoro-4-(4-fluorophenyl)but-2-en-1-amine,(Z)-2-fluoro-4-m-tolylbut-2-en-1-amine,(Z)-2-fluoro-4-(3-fluorophenyl)but-2-en-1-amine,(Z)-2-fluoro-4-(3-methoxyphenyl)but-2-en-1-amine,(Z)-2-fluoro-4-phenylbut-2-en-1-amine,(Z)-2-fluoro-4-(3-(trifluoromethoxy)phenyl)but-2-en-1-amine,(Z)-3-(4-amino-3-fluorobut-2-enyl)-N,N-dimethylbenzenamine,(Z)-4-(3,5-bis(trifluoromethyl)phenyl)-2-fluorobut-2-en-1-amine,(Z)-2-fluoro-4-(3-(methylthio)phenyl)but-2-en-1-amine,(Z)-2-fluoro-4-(3-(methylsulfonyl)phenyl)but-2-en-1-amine,(Z)-2-fluoro-4-(3-(trifluoromethylthio)phenyl)but-2-en-1-amine,(Z)-2-fluoro-4-(3-(methoxymethyl)phenyl)but-2-en-1-amine,(Z)-2-fluoro-4-(2-methoxyphenyl)but-2-en-1-amine,(Z)-2-fluoro-4-(3-methoxyphenyl)-3-methylbut-2-en-1-amine,(Z)-2-fluoro-4-(3-methoxyphenoxy)but-2-en-1-amine,(Z)-2-fluoro-4-(3-methoxyphenylthio)but-2-en-1-amine,(Z)-2-fluoro-4-(3-(trifluoromethyl)phenoxy)but-2-en-1-amine,(Z)-2-fluoro-4-(pyridin-3-yloxy)but-2-en-1-amine, or(Z)-2-fluoro-5-(3-methoxyphenyl)pent-2-en-1-amine, or any stereoisomer,mixture of stereoisomers, prodrug, metabolite, crystalline form,non-crystalline form, hydrate, solvate, or salt thereof.
 26. The methodof claim 17, wherein the inflammation or inflammatory disease or immuneor autoimmune disease is multiple sclerosis, chronic multiple sclerosis,synovitis, systemic inflammatory sepsis, inflammatory bowel diseases,Crohn's disease, ulcerative colitis, Alzheimer's disease, vasculardementia, atherosclerosis, rheumatoid arthritis, juvenile rheumatoidarthritis, pulmonary inflammation, asthma, skin inflammation, contactdermatitis, liver inflammation, liver autoimmune diseases, autoimmunehepatitis, primary biliary cirrhosis, sclerosing cholangitis, autoimmunecholangitis, alcoholic liver disease, Type I diabetes and/orcomplications thereof, Type II diabetes and/or complications thereof,atherosclerosis, chronic heart failure, congestive heart failure,ischemic diseases, stroke and/or complications thereof, or myocardialinfarction and/or complications thereof.
 27. The method of claim 26,wherein the inflammation or inflammatory disease or immune or autoimmunedisease is multiple sclerosis, chronic multiple sclerosis, stroke, orcomplications of stroke.
 28. The method of claim 17, wherein thecompound is of the formula:

or any solvate, hydrate, crystalline form, non-crystalline form, or saltthereof, in a therapeutically effective amount.
 29. A compound of theformula:

wherein Y is aryl or heteroaryl optionally substituted with one or moregroups of the form R₁, wherein each R₁ is independently selected fromC₁-C₈ alkyl, C₃-C₈ cycloalkyl, —O—C₁-C₈ alkyl, —O—C₃-C₈ cycloalkyl,—C₆-C₁₀ aryl, —O—C₁-C₄ alkyl-C₆-C₁₀ aryl, —S—C₁-C₈ alkyl, —CF₃, —S—CF₃,—OCF₃, —OCH₂CF₃, F, Cl, Br, I, —NO₂, —OH, —CN, —NR₅R₆, —NHR₇, and—S(O₂)—(C₁-C₈ alkyl); R₂ is selected from H, F, Cl, C₁-C₄ alkyl, and—CF₃; R₃ and R₄ are independently selected from H, —C₁-C₈ alkyl, —C₁-C₄alkyl-C₆-C₁₀ aryl, or R₃ and R₄ together with the nitrogen to which theyare attached form a nitrogen-containing ring; R₅ and R₆ areindependently selected from H, —C₁-C₈ alkyl, —C₁-C₄ alkyl-C₆-C₁₀ aryl,or R₅ and R₆ together with the nitrogen to which they are attached forma nitrogen-containing ring; R₇ is selected from —C(═O)—(C₁-C₈ alkyl) and—C(═O)—(C₆-C₁₀ aryl); X is —CH₂—, —O—, or —S—; n is 0, 1, 2, or 3; withthe provisos that when Y is phenyl, R₃ and R₄ are both H, X is CH₂, andn is 0, then (a) there is at least one R₁ substituent; (b) if at leastone R₁ substituent is —OCH₃, then there is at least one additional R₁substituent which is not —OCH₃; and (c) if at least one R₁ substituentis —OH, then there is at least one additional R₁ substituent which isnot —OH; with the additional proviso that when Y is phenyl, R₃ and R₄are both H, X is O or S, and n is 1, then (a) there is at least one R₁substituent; (b) the phenyl substituents are not Cl, —CF₃, or F in theortho or para position; (c) the phenyl substituents are not3-chloro-5-fluoro and (d) if at least one R₁ substituent is —OCH₃, thenthere is at least one additional R₁ substituent which is not —OCH₃; and(e) if at least one R₁ substituent is —OH, then there is at least oneadditional R₁ substituent which is not —OH; with the additional provisothat when Y is phenyl, R₃ and R₄ are both H, X is CH₃, and n is 1, then(a) there is at least one R₁ substituent; and (b) the phenyl substituentis not F in the para position; with the additional proviso that when Yis phenyl, R₃ and R₄ are both H, X is CH₃, and n is 2, then the phenylsubstituents are not 3,4-dimethoxy; and any stereoisomer, mixture ofstereoisomers, prodrug, metabolite, crystalline form, non-crystallineform, hydrate, solvate, or salt thereof.
 30. A compound of claim 29,wherein the X is CH₂ and n is
 0. 31. A compound of claim 29, wherein theX is CH₂ and n is
 1. 32. A compound of claim 29, wherein the X is O andn is
 0. 33. A compound of claim 29, wherein Y is phenyl, optionallysubstituted with one or more groups of the form R₁.
 34. A compound ofclaim 29, wherein R₃ and R₄ are both H.
 35. A compound of claim 29,wherein the double bond is in the Z configuration.
 36. A compound ofclaim 29, wherein the double bond is in the E configuration.
 37. Acompound of claim 29, wherein the R₂ is F.
 38. A compound of claim 29,wherein the R₂ is Cl.
 39. A compound of claim 29 which is:(Z)-2-(4-ethoxybenzyl)-3-fluoroprop-2-en-1-amine,(Z)-2-(4-chlorobenzyl)-3-fluoroprop-2-en-1-amine,(Z)-2-(3-chlorobenzyl)-3-fluoroprop-2-en-1-amine,(Z)-3-fluoro-2-(4-isopropoxybenzyl)prop-2-en-1-amine,(Z)-3-fluoro-2-(4-(methylthio)benzyl)prop-2-en-1-amine,(Z)-3-fluoro-2-(3-(methylthio)benzyl)prop-2-en-1-amine,(Z)-3-fluoro-2-(4-(methylsulfonyl)benzyl)prop-2-en-1-amine,(Z)-3-fluoro-2-(4-methylbenzyl)prop-2-en-1-amine,(Z)-3-fluoro-2-(3-methylbenzyl)prop-2-en-1-amine,(Z)-3-fluoro-2-(4-isopropylbenzyl)prop-2-en-1-amine,(Z)-2-(4-tert-butylbenzyl)-3-fluoroprop-2-en-1-amine,(Z)-2-(biphenyl-4-ylmethyl)-3-fluoroprop-2-en-1-amine,(Z)-3-fluoro-2-(4-fluorobenzyl)prop-2-en-1-amine,(Z)-3-fluoro-2-(3-(trifluoromethyl)benzyl)prop-2-en-1-amine,(Z)-3-fluoro-2-(3-fluorobenzyl)prop-2-en-1-amine,(Z)-3-fluoro-2-(3-fluoro-4-methylbenzyl)prop-2-en-1-amine,(Z)-3-fluoro-2-(3-fluoro-4-methoxybenzyl)prop-2-en-1-amine,(Z)-3-fluoro-2-(4-fluoro-3-methylbenzyl)prop-2-en-1-amine,(Z)-2-(3-chloro-4-fluorobenzyl)-3-fluoroprop-2-en-1-amine,(Z)-2-(2,5-difluorobenzyl)-3-fluoroprop-2-en-1-amine,(Z)-2-(3-chloro-5-fluorobenzyl)-3-fluoroprop-2-en-1-amine,(Z)-2-(2,4-difluorobenzyl)-3-fluoroprop-2-en-1-amine, (Z)-2-(3,5-dichlorobenzyl)-3-fluoroprop-2-en-1-amine,(Z)-2-(3,4-difluorobenzyl)-3-fluoroprop-2-en-1-amine,(Z)-2-(chloromethylene)-4-(4-fluorophenyl)butan-1-amine,(Z)-2-(chloromethylene)-4-(4-chlorophenyl)butan-1-amine,(Z)-2-(chloromethylene)-4-(4-methoxyphenyl)butan-1-amine,(Z)-2-(chloromethylene)-4-(4-ethoxyphenyl)butan-1-amine,(Z)-2-(chloromethylene)-4-(4-(trifluoromethyl)phenyl)butan-1-amine,(Z)-4-(4-butoxyphenyl)-2-(chloromethylene)butan-1-amine,(Z)-2-(chloromethylene)-4-m-tolylbutan-1-amine,(Z)-2-(chloromethylene)-4-(3-methoxyphenyl)butan-1-amine,(Z)-2-(chloromethylene)-4-p-tolylbutan-1-amine,(Z)-2-(chloromethylene)-4-(3-fluoro-5-(trifluoromethyl)phenyl)butan-1-amine,(Z)-2-(chloromethylene)-4-(4-fluorophenyl)butan-1-amine,(Z)-2-(chloromethylene)-4-(4-chlorophenyl)butan-1-amine,(Z)-2-(chloromethylene)-4-(4-methoxyphenyl)butan-1-amine,(Z)-2-(chloromethylene)-4-(4-ethoxyphenyl)butan-1-amine,(Z)-2-(chloromethylene)-4-(4-(trifluoromethyl)phenyl)butan-1-amine,(Z)-4-(4-butoxyphenyl)-2-(chloromethylene)butan-1-amine,(Z)-2-(chloromethylene)-4-m-tolylbutan-1-amine,(Z)-2-(chloromethylene)-4-(3-methoxyphenyl)butan-1-amine,(Z)-2-(chloromethylene)-4-p-tolylbutan-1-amine,(Z)-2-(chloromethylene)-4-(3-fluoro-5-(trifluoromethyl)phenyl)butan-1-amine,(Z)-2-(4-(cyclopropylmethoxy)benzyl)-3-fluoroprop-2-en-1-amine,(Z)-2-(4-(cyclopropylmethoxy)-3-fluorobenzyl)-3-fluoroprop-2-en-1-amine,(Z)-3-fluoro-2-(3-fluoro-4-(pentyloxy)benzyl)prop-2-en-1-amine,(Z)-3-fluoro-2-(2,3,5,6-tetrafluoro-4-methoxybenzyl)prop-2-en-1-amine,(Z)-2-(4-ethoxy-3-fluorobenzyl)-3-fluoroprop-2-en-1-amine,(Z)-2-(2,3-difluoro-4-methoxybenzyl)-3-fluoroprop-2-en-1-amine,(Z)-2-(4-(benzyloxy)-3-fluorobenzyl)-3-fluoroprop-2-en-1-amine,(Z)-3-fluoro-2-(4-fluoro-3-(trifluoromethoxy)benzyl)prop-2-en-1-amine,(Z)-3-fluoro-2-(4-(2,2,2-trifluoroethoxy)benzyl)prop-2-en-1-amine,(Z)-2-(3,5-difluoro-4-methoxybenzyl)-3-fluoroprop-2-en-1-amine,(Z)-2-(3-ethoxybenzyl)-3-fluoroprop-2-en-1-amine,(Z)-3-fluoro-2-(3-isopropoxybenzyl)prop-2-en-1-amine,(Z)-3-fluoro-2-(3-(trifluoromethoxy)benzyl)prop-2-en-1-amine,(Z)-2-(3-(cyclopropylmethoxy)benzyl)-3-fluoroprop-2-en-1-amine,(Z)-2-(3-(benzyloxy)benzyl)-3-fluoroprop-2-en-1-amine,(Z)-3-fluoro-2-(2-fluoro-5-(trifluoromethoxy)benzyl)prop-2-en-1-amine,(Z)-2-(3-chloro-5-(trifluoromethoxy)benzyl)-3-fluoroprop-2-en-1-amine,(Z)-3-fluoro-2-(2,3,5-trifluorobenzyl)prop-2-en-1-amine,(Z)-3-fluoro-2-(3,4,5-trifluorobenzyl)prop-2-en-1-amine,(Z)-3-(2-(aminomethyl)-3-fluoroallyl)benzonitrile,(Z)-2-(4-bromobenzyl)-3-fluoroprop-2-en-1-amine,(Z)-2-(3-bromobenzyl)-3-fluoroprop-2-en-1-amine,(Z)-3-fluoro-2-(pyridin-2-ylmethyl)prop-2-en-1-amine,(Z)-3-fluoro-2-(pyridin-3-ylmethyl)prop-2-en-1-amine,(Z)-3-fluoro-2-(naphthalen-2-ylmethyl)prop-2-en-1-amine,(Z)-2-(benzofuran-2-ylmethyl)-3-fluoroprop-2-en-1-amine,(Z)-2-(benzofuran-3-ylmethyl)-3-fluoroprop-2-en-1-amine,(Z)-3-fluoro-2-(quinolin-3-ylmethyl)prop-2-en-1-amine,(Z)-2-(benzo[b]thiophen-3-ylmethyl)-3-fluoroprop-2-en-1-amine,(Z)-2-(benzo[b]thiophen-2-ylmethyl)-3-fluoroprop-2-en-1-amine,(E)-2-((4-ethoxyphenoxy)methyl)-3-fluoroprop-2-en-1-amine,(E)-2-((4-butoxyphenoxy)methyl)-3-fluoroprop-2-en-1-amine,(E)-3-fluoro-2-(m-tolyloxymethyl)prop-2-en-1-amine,(E)-3-fluoro-2-(p-tolyloxymethyl)prop-2-en-1-amine,(E)-3-fluoro-2-((3-fluoro-5-(trifluoromethyl)phenoxy)methyl)prop-2-en-1-amine,(Z)-3-fluoro-2-(furan-2-ylmethyl)prop-2-en-1-amine,(Z)-3-fluoro-2-(thiophen-2-ylmethyl)prop-2-en-1-amine,(Z)-2-((5-chlorothiophen-2-yl)methyl)-3-fluoroprop-2-en-1-amine,(Z)-3-fluoro-2-((5-methylthiophen-2-yl)methyl)prop-2-en-1-amine,(Z)-3-fluoro-2-(furan-3-ylmethyl)prop-2-en-1-amine,(Z)-3-fluoro-2-(thiophen-3-ylmethyl)prop-2-en-1-amine,(Z)-2-((5-chlorothiophen-3-yl)methyl)-3-fluoroprop-2-en-1-amine,(Z)-2-(fluoromethylene)-4-(3-fluorophenyl)butan-1-amine,(Z)-4-(4-chlorophenyl)-2-(fluoromethylene)butan-1-amine,(Z)-2-(fluoromethylene)-4-(4-methoxyphenyl)butan-1-amine,(Z)-4-(4-ethoxyphenyl)-2-(fluoromethylene)butan-1-amine,(Z)-2-(fluoromethylene)-4-(4-(trifluoromethyl)phenyl)butan-1-amine,(Z)-4-(4-butoxyphenyl)-2-(fluoromethylene)butan-1-amine,(Z)-2-(fluoromethylene)-4-m-tolylbutan-1-amine,(Z)-2-(fluoromethylene)-4-(3-methoxyphenyl)butan-1-amine,(Z)-2-(fluoromethylene)-4-p-tolylbutan-1-amine, or(Z)-4-(3-fluoro-5-(trifluoromethyl)phenyl)-2-(fluoromethylene)butan-1-amine,or any stereoisomer, mixture of stereoisomers, prodrug, metabolite,crystalline form, non-crystalline form, hydrate, solvate, or saltthereof.
 40. A compound of claim 29 which is:(E)-2-(4-ethoxybenzyl)-3-fluoroprop-2-en-1-amine,(E)-2-(4-chlorobenzyl)-3-fluoroprop-2-en-1-amine,(E)-2-(3-chlorobenzyl)-3-fluoroprop-2-en-1-amine,(E)-3-fluoro-2-(4-isopropoxybenzyl)prop-2-en-1-amine,(E)-3-fluoro-2-(4-(methylthio)benzyl)prop-2-en-1-amine,(E)-3-fluoro-2-(3-(methylthio)benzyl)prop-2-en-1-amine,(E)-3-fluoro-2-(4-(methylsulfonyl)benzyl)prop-2-en-1-amine,(E)-3-fluoro-2-(4-methylbenzyl)prop-2-en-1-amine,(E)-3-fluoro-2-(3-methylbenzyl)prop-2-en-1-amine,(E)-3-fluoro-2-(4-isopropylbenzyl)prop-2-en-1-amine,(E)-2-(4-tert-butylbenzyl)-3-fluoroprop-2-en-1-amine,(E)-2-(biphenyl-4-ylmethyl)-3-fluoroprop-2-en-1-amine,(E)-3-fluoro-2-(4-fluorobenzyl)prop-2-en-1-amine,(E)-3-fluoro-2-(3-(trifluoromethyl)benzyl)prop-2-en-1-amine,(E)-3-fluoro-2-(3-fluorobenzyl)prop-2-en-1-amine,(E)-3-fluoro-2-(3-fluoro-4-methylbenzyl)prop-2-en-1-amine,(E)-3-fluoro-2-(3-fluoro-4-methoxybenzyl)prop-2-en-1-amine,(E)-3-fluoro-2-(4-fluoro-3-methylbenzyl)prop-2-en-1-amine,(E)-2-(3-chloro-4-fluorobenzyl)-3-fluoroprop-2-en-1-amine,(E)-2-(2,5-difluorobenzyl)-3-fluoroprop-2-en-1-amine,(E)-2-(3-chloro-5-fluorobenzyl)-3-fluoroprop-2-en-1-amine,(E)-2-(2,4-difluorobenzyl)-3-fluoroprop-2-en-1-amine,(E)-2-(3,5-dichlorobenzyl)-3-fluoroprop-2-en-1-amine,(E)-2-(3,4-difluorobenzyl)-3-fluoroprop-2-en-1-amine,(E)-2-(chloromethylene)-4-(4-fluorophenyl)butan-1-amine,(E)-2-(chloromethylene)-4-(4-chlorophenyl)butan-1-amine,(E)-2-(chloromethylene)-4-(4-methoxyphenyl)butan-1-amine,(E)-2-(chloromethylene)-4-(4-ethoxyphenyl)butan-1-amine,(E)-2-(chloromethylene)-4-(4-(trifluoromethyl)phenyl)butan-1-amine,(E)-4-(4-butoxyphenyl)-2-(chloromethylene)butan-1-amine,(E)-2-(chloromethylene)-4-m-tolylbutan-1-amine,(E)-2-(chloromethylene)-4-(3-methoxyphenyl)butan-1-amine,(E)-2-(chloromethylene)-4-p-tolylbutan-1-amine,(E)-2-(chloromethylene)-4-(3-fluoro-5-(trifluoromethyl)phenyl)butan-1-amine,(E)-2-(chloromethylene)-4-(4-fluorophenyl)butan-1-amine,(E)-2-(chloromethylene)-4-(4-chlorophenyl)butan-1-amine,(E)-2-(chloromethylene)-4-(4-methoxyphenyl)butan-1-amine,(E)-2-(chloromethylene)-4-(4-ethoxyphenyl)butan-1-amine,(E)-2-(chloromethylene)-4-(4-(trifluoromethyl)phenyl)butan-1-amine,(E)-4-(4-butoxyphenyl)-2-(chloromethylene)butan-1-amine,(E)-2-(chloromethylene)-4-m-tolylbutan-1-amine,(E)-2-(chloromethylene)-4-(3-methoxyphenyl)butan-1-amine,(E)-2-(chloromethylene)-4-p-tolylbutan-1-amine,(E)-2-(chloromethylene)-4-(3-fluoro-5-(trifluoromethyl)phenyl)butan-1-amine,(E)-2-(4-(cyclopropylmethoxy)benzyl)-3-fluoroprop-2-en-1-amine,(E)-2-(4-(cyclopropylmethoxy)-3-fluorobenzyl)-3-fluoroprop-2-en-1-amine,(E)-3-fluoro-2-(3-fluoro-4-(pentyloxy)benzyl)prop-2-en-1-amine,(E)-3-fluoro-2-(2,3,5,6-tetrafluoro-4-methoxybenzyl)prop-2-en-1-amine,(E)-2-(4-ethoxy-3-fluorobenzyl)-3-fluoroprop-2-en-1-amine,(E)-2-(2,3-difluoro-4-methoxybenzyl)-3-fluoroprop-2-en-1-amine,(E)-2-(4-(benzyloxy)-3-fluorobenzyl)-3-fluoroprop-2-en-1-amine,(E)-3-fluoro-2-(4-fluoro-3-(trifluoromethoxy)benzyl)prop-2-en-1-amine,(E)-3-fluoro-2-(4-(2,2,2-trifluoroethoxy)benzyl)prop-2-en-1-amine,(E)-2-(3,5-difluoro-4-methoxybenzyl)-3-fluoroprop-2-en-1-amine,(E)-2-(3-ethoxybenzyl)-3-fluoroprop-2-en-1-amine,(E)-3-fluoro-2-(3-isopropoxybenzyl)prop-2-en-1-amine,(E)-3-fluoro-2-(3-(trifluoromethoxy)benzyl)prop-2-en-1-amine,(E)-2-(3-(cyclopropylmethoxy)benzyl)-3-fluoroprop-2-en-1-amine,(E)-2-(3-(benzyloxy)benzyl)-3-fluoroprop-2-en-1-amine,(E)-3-fluoro-2-(2-fluoro-5-(trifluoromethoxy)benzyl)prop-2-en-1-amine,(E)-2-(3-chloro-5-(trifluoromethoxy)benzyl)-3-fluoroprop-2-en-1-amine,(E)-3-fluoro-2-(2,3,5-trifluorobenzyl)prop-2-en-1-amine,(E)-3-fluoro-2-(3,4,5-trifluorobenzyl)prop-2-en-1-amine,(E)-3-(2-(aminomethyl)-3-fluoroallyl)benzonitrile,(E)-2-(4-bromobenzyl)-3-fluoroprop-2-en-1-amine,(E)-2-(3-bromobenzyl)-3-fluoroprop-2-en-1-amine,(E)-3-fluoro-2-(pyridin-2-ylmethyl)prop-2-en-1-amine,(E)-3-fluoro-2-(pyridin-3-ylmethyl)prop-2-en-1-amine,(E)-3-fluoro-2-(naphthalen-2-ylmethyl)prop-2-en-1-amine,(E)-2-(benzofuran-2-ylmethyl)-3-fluoroprop-2-en-1-amine,(E)-2-(benzofuran-3-ylmethyl)-3-fluoroprop-2-en-1-amine,(E)-3-fluoro-2-(quinolin-3-ylmethyl)prop-2-en-1-amine,(E)-2-(benzo[b]thiophen-3-ylmethyl)-3-fluoroprop-2-en-1-amine,(E)-2-(benzo[b]thiophen-2-ylmethyl)-3-fluoroprop-2-en-1-amine,(Z)-2-((4-ethoxyphenoxy)methyl)-3-fluoroprop-2-en-1-amine,(Z)-2-((4-butoxyphenoxy)methyl)-3-fluoroprop-2-en-1-amine,(Z)-3-fluoro-2-(m-tolyloxymethyl)prop-2-en-1-amine,(Z)-3-fluoro-2-(p-tolyloxymethyl)prop-2-en-1-amine,(Z)-3-fluoro-2-((3-fluoro-5-(trifluoromethyl)phenoxy)methyl)prop-2-en-1-amine,(E)-3-fluoro-2-(furan-2-ylmethyl)prop-2-en-1-amine,(E)-3-fluoro-2-(thiophen-2-ylmethyl)prop-2-en-1-amine,(E)-2-((5-chlorothiophen-2-yl)methyl)-3-fluoroprop-2-en-1-amine,(E)-3-fluoro-2-((5-methylthiophen-2-yl)methyl)prop-2-en-1-amine,(E)-3-fluoro-2-(furan-3-ylmethyl)prop-2-en-1-amine,(E)-3-fluoro-2-(thiophen-3-ylmethyl)prop-2-en-1-amine,(E)-2-((5-chlorothiophen-3-yl)methyl)-3-fluoroprop-2-en-1-amine,(E)-2-(fluoromethylene)-4-(3-fluorophenyl)butan-1-amine,(E)-4-(4-chlorophenyl)-2-(fluoromethylene)butan-1-amine,(E)-2-(fluoromethylene)-4-(4-methoxyphenyl)butan-1-amine,(E)-4-(4-ethoxyphenyl)-2-(fluoromethylene)butan-1-amine,(E)-2-(fluoromethylene)-4-(4-(trifluoromethyl)phenyl)butan-1-amine,(E)-4-(4-butoxyphenyl)-2-(fluoromethylene)butan-1-amine,(E)-2-(fluoromethylene)-4-m-tolylbutan-1-amine,(E)-2-(fluoromethylene)-4-(3-methoxyphenyl)butan-1-amine,(E)-2-(fluoromethylene)-4-p-tolylbutan-1-amine, or(E)-4-(3-fluoro-5-(trifluoromethyl)phenyl)-2-(fluoromethylene)butan-1-amine,or any stereoisomer, mixture of stereoisomers, prodrug, metabolite,crystalline form, non-crystalline form, hydrate, solvate, or saltthereof.
 41. The compound of claim 29 of formula:

or any stereoisomer, mixture of stereoisomers, prodrug, metabolite,crystalline form, non-crystalline form, hydrate, solvate, or saltthereof.
 42. The compound of claim 29 of formula:

or any stereoisomer, mixture of stereoisomers, prodrug, metabolite,crystalline form, non-crystalline form, hydrate, solvate, or saltthereof.
 43. A compound of the formula:

wherein Y is a phenyl, naphthyl, or pyridyl group optionally substitutedwith one or more groups of the form R₁, wherein each R₁ is independentlyselected from H, C₁-C₈ alkyl, C₃-C₈ cycloalkyl, —O—C₁-C₈ alkyl, —O—C₃-C₈cycloalkyl, —C₆-C₁₀ aryl, —O—C₁-C₄ alkyl-C₆-C₁₀ aryl, —S—C₁-C₈ alkyl,—CF₃, —OCF₃, F, Cl, Br, I, —NO₂, —OH, —NR₅R₆, —NHR₇, and —S(O₂)—(C₁-C₈alkyl); R₂ is selected from H, F, Cl, C₁-C₄ alkyl, and CF₃; R₃ and R₄are independently selected from H, —C₁-C₈ alkyl, —C₁-C₄ alkyl-C₆-C₁₀aryl, or R₃ and R₄ together with the nitrogen to which they are attachedform a nitrogen-containing ring; R₅ and R₆ are independently selectedfrom H, —C₁-C₈ alkyl, —C₁-C₄ alkyl-C₆-C₁₀ aryl, or R₅ and R₆ togetherwith the nitrogen to which they are attached form a nitrogen-containingring; R₇ is selected from —C(═O)—(C₁-C₈ alkyl) and —C(═O)—(C₆-C₁₀ aryl);R₈ is selected from H, C₁-C₈ alkyl, C₆-C₁₀ aryl, —C₁-C₄ alkyl-C₆-C₁₀aryl, and —CF₃; X is —CH₂—, —O—, or —S—; n is 0, 1, 2, or 3; and p is 0,1, 2, or 3; and any stereoisomer, mixture of stereoisomers, prodrug,metabolite, crystalline form, non-crystalline form, hydrate, solvate, orsalt thereof.
 44. A compound of claim 43, wherein X is CH₂ and n is 0.45. A compound of claim 43, wherein X is CH₂ and n is
 1. 46. A compoundof claim 43, wherein Y is phenyl, optionally substituted with one ormore groups of the form R₁.
 47. A compound of claim 43, wherein R₃ andR₄ are both H.
 48. A compound of claim 43, wherein X is O or S and nis
 1. 49. A compound of claim 43, wherein the double bond is in the Econfiguration.
 50. A compound of claim 43, wherein the double bond is inthe Z configuration.
 51. A compound of claim 43 which is:(E)-2-fluoro-4-(3-fluoro-5-(trifluoromethyl)phenyl)but-2-en-1-amine,(E)-2-fluoro-4-(3-(trifluoromethyl)phenyl)but-2-en-1-amine,(E)-2-fluoro-4-(4-methoxyphenyl)but-2-en-1-amine,(E)-2-fluoro-4-(4-methoxy-3-(trifluoromethyl)phenyl)but-2-en-1-amine,(E)-2-fluoro-4-(4-fluorophenyl)but-2-en-1-amine,(E)-2-fluoro-4-m-tolylbut-2-en-1-amine,(E)-2-fluoro-4-(3-fluorophenyl)but-2-en-1-amine,(E)-2-fluoro-4-(3-methoxyphenyl)but-2-en-1-amine,(E)-2-fluoro-4-phenylbut-2-en-1-amine,(E)-2-fluoro-4-(3-(trifluoromethoxy)phenyl)but-2-en-1-amine,(E)-3-(4-amino-3-fluorobut-2-enyl)-N,N-dimethylbenzenamine,(E)-4-(3,5-bis(trifluoromethyl)phenyl)-2-fluorobut-2-en-1-amine,(E)-2-fluoro-4-(3-(methylthio)phenyl)but-2-en-1-amine,(E)-2-fluoro-4-(3-(methylsulfonyl)phenyl)but-2-en-1-amine,(E)-2-fluoro-4-(3-(trifluoromethylthio)phenyl)but-2-en-1-amine,(E)-2-fluoro-4-(3-(methoxymethyl)phenyl)but-2-en-1-amine,(E)-2-fluoro-4-(2-methoxyphenyl)but-2-en-1-amine,(E)-2-fluoro-4-(3-methoxyphenyl)-3-methylbut-2-en-1-amine,(E)-2-fluoro-4-(3-methoxyphenoxy)but-2-en-1-amine,(E)-2-fluoro-4-(3-methoxyphenylthio)but-2-en-1-amine,(E)-2-fluoro-4-(3-(trifluoromethyl)phenoxy)but-2-en-1-amine,(E)-2-fluoro-4-(pyridin-3-yloxy)but-2-en-1-amine, or(E)-2-fluoro-5-(3-methoxyphenyl)pent-2-en-1-amine, or any stereoisomer,mixture of stereoisomers, prodrug, metabolite, crystalline form,non-crystalline form, hydrate, solvate, or salt thereof.
 52. A compoundof claim 43 which is:(Z)-2-fluoro-4-(3-fluoro-5-(trifluoromethyl)phenyl)but-2-en-1-amine,(Z)-2-fluoro-4-(3-(trifluoromethyl)phenyl)but-2-en-1-amine,(Z)-2-fluoro-4-(4-methoxyphenyl)but-2-en-1-amine,(Z)-2-fluoro-4-(4-methoxy-3-(trifluoromethyl)phenyl)but-2-en-1-amine,(Z)-2-fluoro-4-(4-fluorophenyl)but-2-en-1-amine,(Z)-2-fluoro-4-m-tolylbut-2-en-1-amine,(Z)-2-fluoro-4-(3-fluorophenyl)but-2-en-1-amine,(Z)-2-fluoro-4-(3-methoxyphenyl)but-2-en-1-amine,(Z)-2-fluoro-4-phenylbut-2-en-1-amine,(Z)-2-fluoro-4-(3-(trifluoromethoxy)phenyl)but-2-en-1-amine,(Z)-3-(4-amino-3-fluorobut-2-enyl)-N,N-dimethylbenzenamine,(Z)-4-(3,5-bis(trifluoromethyl)phenyl)-2-fluorobut-2-en-1-amine,(Z)-2-fluoro-4-(3-(methylthio)phenyl)but-2-en-1-amine,(Z)-2-fluoro-4-(3-(methylsulfonyl)phenyl)but-2-en-1-amine,(Z)-2-fluoro-4-(3-(trifluoromethylthio)phenyl)but-2-en-1-amine,(Z)-2-fluoro-4-(3-(methoxymethyl)phenyl)but-2-en-1-amine,(Z)-2-fluoro-4-(2-methoxyphenyl)but-2-en-1-amine,(Z)-2-fluoro-4-(3-methoxyphenyl)-3-methylbut-2-en-1-amine,(Z)-2-fluoro-4-(3-methoxyphenoxy)but-2-en-1-amine,(Z)-2-fluoro-4-(3-methoxyphenylthio)but-2-en-1-amine,(Z)-2-fluoro-4-(3-(trifluoromethyl)phenoxy)but-2-en-1-amine,(Z)-2-fluoro-4-(pyridin-3-yloxy)but-2-en-1-amine, or(Z)-2-fluoro-5-(3-methoxyphenyl)pent-2-en-1-amine, or any stereoisomer,mixture of stereoisomers, prodrug, metabolite, crystalline form,non-crystalline form, hydrate, solvate, or salt thereof.
 53. Thecompound of claim 43 of formula:

or any stereoisomer, mixture of stereoisomers, prodrug, metabolite,crystalline form, non-crystalline form, hydrate, solvate, or saltthereof.